Horizon Scan Of Clinical Laboratories Offering Pharmacogenetic Testing.

Health Aff (Millwood). 2018 05;37(5):717-723

Authors: Haga SB, Kantor A

Abstract
Pharmacogenetic (PGx) testing involves the analysis of genes known to affect response to medications. The field has been projected as a leading application of personalized or precision medicine, but the use of PGx tests has been stymied, in part, by the lack of clinical evidence of utility and reported low provider awareness. Another factor is the availability of testing. The range and types of PGx tests available have not been assessed to date. In the period September 2017-January 2018 we analyzed the numbers and types of PGx tests offered by clinical testing laboratories in the US. Of the 111 such labs that we identified, we confirmed that 76 offered PGx testing services. Of these, 31 offered only tests for single genes; 30 offered only tests for multiple genes; and 15 offered both types of tests. Collectively, 45 laboratories offered 114 multigene panel tests covering 295 genes. The majority of these tests did not have any clinical guidelines. PGx tests vary in type and makeup, which presents challenges in appropriate test evaluation and selection for providers, insurers, health systems, and patients alike.

PMID: 29733708 [PubMed - indexed for MEDLINE]

Views Of Primary Care Providers On Testing Patients For Genetic Risks For Common Chronic Diseases.

Health Aff (Millwood). 2018 05;37(5):793-800

Authors: Hauser D, Obeng AO, Fei K, Ramos MA, Horowitz CR

Abstract
We surveyed 488 primary care providers in community and academic practices in New York City in the period 2014-16 about their views on genetic testing for chronic diseases. The majority of the providers, most of whom were current or recent physicians in training, had had formal genetics education and had positive views of the utility of genetic testing. However, they felt unprepared to work with patients at high risk for genetic conditions and were not confident about interpreting test results. Many were concerned that genetic testing might lead to insurance discrimination and lacked trust in companies that offer genetic tests. These findings point to some of the attitudes and knowledge gaps among the providers that should be considered in the clinical implementation of genomic medicine for chronic conditions. Enhanced training, guidelines, clinical tools, and awareness of patient protections might support the effective adoption of genomic medicine by primary care providers.

PMID: 29733703 [PubMed - indexed for MEDLINE]

Introduction to Genomics: A Primer.

Semin Oncol Nurs. 2019 Jan 16;:

Authors: Flynn S

Abstract
OBJECTIVE: To review basic oncology genetic/genomic terminology through a 10-question quiz.
DATA SOURCES: Published literature, national guidelines, and Web sites.
CONCLUSION: Cancer care now requires the integration of genetic/genomic information into the daily practice of oncology nurses.
IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses and health care providers can work to improve the care of oncology patients by understanding basic genetics/genomics topics such as cancer risk assessment, hereditary cancer syndromes, pharmacogenomics, epigenetics, and legislation to protect genetic testing results.

PMID: 30660357 [PubMed - as supplied by publisher]

Sudden unexpected death in GEFS+ families with sodium channel pathogenic variants.

Epilepsy Res. 2019 Jan 14;150:66-69

Authors: Myers KA, Shevell MI, Sébire G

Abstract
We aimed to describe families with genetic epilepsy with febrile seizures plus (GEFS+) in which individuals suffered sudden unexpected death. The Epilepsy Pharmacogenomics Research Database was reviewed for GEFS + families in which at least one individual had suffered sudden death, and two families were identified. In Family A, five males had febrile seizures and one girl had febrile seizures plus. The latter died at 22 months of age and was classified as definite SUDEP. Molecular genetic testing identified a pathogenic SCN1B variant. In Family B, two brothers had recurrent focal status epilepticus with fever, and were classified as having atypical multifocal Dravet syndrome. The elder brother died suddenly at seven years of age, but was not classified SUDEP because the event occurred following status epilepticus. SCN1A sequencing in the surviving brother identified a likely pathogenic variant. These two cases of sudden death in GEFS + families with likely pathogenic variants in sodium channel genes demonstrate that sudden death may occur in GEFS+, even with mild phenotypes. The presence of sodium channel variants may have further increased the sudden death risk, particularly in the case of SCN1B, a gene which has also been associated with cardiac conditions including Brugada syndrome and long QT.

PMID: 30660056 [PubMed - as supplied by publisher]

Genotype tailored treatment of mild symptomatic acid reflux in children with uncontrolled asthma (GenARA): Rationale and methods.

Contemp Clin Trials. 2019 Jan 16;:

Authors: Tang M, Blake KV, Lima JJ, Mougey EB, Franciosi J, Schmidt S, Hossain MJ, Cobbaert M, Fischer BM, Lang JE

Abstract
Asthma causes enormous suffering and cost for children in the US and around the world [1-3]. Co-morbid gastroesophageal reflux disease (GERD) makes asthma management more difficult due to increased symptoms. Proton pump inhibitor (PPI) drugs are effective at improving to GERD symptoms, however they have demonstrated only modest and variable effects on asthma control in the setting of co-morbid GERD. Importantly, PPI metabolism and efficacy depend on CYP2C19 genotype. The Genotype Tailored Treatment of Symptomatic Acid Reflux in Children with Uncontrolled Asthma (GenARA) study is a randomized, double-blind, placebo-controlled trial to determine if genotype-tailored PPI dosing improves asthma symptoms among children with inadequately controlled asthma and GERD symptoms. This study has an innovative design to both assess the efficacy of genotype-tailored PPI dosing and perform pharmacokinetic modeling of the oral PPI Lansoprazole. Children ages 6-17 years old with clinician-diagnosed asthma and mild GERD symptoms will submit a saliva sample for CYP2C19 genotyping. Participants will undergo a two-step randomization to: (1) genotype-tailored versus conventional dosing of open-label oral lansoprazole for pharmacokinetic modeling, and (2) genotype-tailored lansoprazole daily versus placebo for 24 weeks to determine the effect of genotype-tailored PPI dosing on asthma control. Measures of asthma control, spirometry, and nasal washes during acute illnesses will be collected at 8-week intervals throughout the study. GenARA will better define the effects of CYP2C19 genotype on the dose response of lansoprazole in children and adolescents and assess if a novel dosing regimen improves GERD and asthma control.

PMID: 30659924 [PubMed - as supplied by publisher]

Correction: The influence of FCGR2A and FCGR3A polymorphisms on the survival of patients with recurrent or metastatic squamous cell head and neck cancer treated with cetuximab.

Pharmacogenomics J. 2019 Jan 18;:

Authors: Magnes T, Melchardt T, Hufnagl C, Weiss L, Mittermair C, Neureiter D, Klieser E, Rinnerthaler G, Roesch S, Gaggl A, Greil R, Egle A

Abstract
In the abstract and in other parts of the manuscript the authors wrote that the mutation rs396991 causes a valine (V) to phenylalanine (F) substitution at position 157. However, the correct codon number is 158. These errors have not been fixed in the original Article.

PMID: 30659276 [PubMed - as supplied by publisher]

Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants.

J Pers Med. 2019 Jan 17;9(1):

Authors: Kanuri SH, Kreutz RP

Abstract
Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

PMID: 30658513 [PubMed]

Genomes of Three Closely Related Caribbean Amazons Provide Insight for Species History and Conservation.

Genes (Basel). 2019 Jan 16;10(1):

Authors: Kolchanova S, Kliver S, Komissarov A, Dobrinin P, Tamazian G, Grigorev K, Wolfsberger WW, Majeske AJ, Velez-Valentin J, Valentin de la Rosa R, Paul-Murphy JR, Guzman DS, Court MH, Rodriguez-Flores JL, Martínez-Cruzado JC, Oleksyk TK

Abstract
Islands have been used as model systems for studies of speciation and extinction since Darwin published his observations about finches found on the Galapagos. Amazon parrots inhabiting the Greater Antillean Islands represent a fascinating model of species diversification. Unfortunately, many of these birds are threatened as a result of human activity and some, like the Puerto Rican parrot, are now critically endangered. In this study we used a combination of de novo and reference-assisted assembly methods, integrating it with information obtained from related genomes to perform genome reconstruction of three amazon species. First, we used whole genome sequencing data to generate a new de novo genome assembly for the Puerto Rican parrot (Amazona vittata). We then improved the obtained assembly using transcriptome data from Amazona ventralis and used the resulting sequences as a reference to assemble the genomes Hispaniolan (A. ventralis) and Cuban (Amazona leucocephala) parrots. Finally, we, annotated genes and repetitive elements, estimated genome sizes and current levels of heterozygosity, built models of demographic history and provided interpretation of our findings in the context of parrot evolution in the Caribbean.

PMID: 30654561 [PubMed]

Metformin suppresses UHMWPE particle-induced osteolysis in the mouse calvaria by promoting polarization of macrophages to an anti-inflammatory phenotype.

Mol Med. 2018 05 09;24(1):20

Authors: Yan Z, Tian X, Zhu J, Lu Z, Yu L, Zhang D, Liu Y, Yang C, Zhu Q, Cao X

Abstract
BACKGROUND: Implant failure remains a major obstacle to successful treatment via TJA. Periprosthetic osteolysis and aseptic loosening are considered as proof of wear debris-induced disruption of local regulatory mechanisms related to excessive bone resorption associated with osteolysis and the damage at the bone-prosthesis interface. Therefore, there is an immediate need to explore strategies for limiting and curing periprosthetic osteolysis and aseptic loosening.
METHODS: We analyzed the in vitro cytokine production by primary mouse bone marrow macrophages (BMMs) that were exposed to ultra-high molecular weight polyethylene (UHMWPE) particles and treated with metformin at different concentrations with or without 5-aminoimidazole-4-carboxamide ribonucleoside to activate or inhibit AMPK. A mouse calvarial model was used to examine the in vivo effects of metformin on UHMWPE particle-induced osteolysis.
RESULTS: With particles, primary mouse BMMs secreted more pro-inflammatory cytokines tumor necrosis factor-α and interleukin (IL)-6. Treatment with metformin inhibited these variations and promoted the release of cytokine IL-10 with anti-inflammatory capability. In vivo, metformin reduced the production of pro-inflammatory cytokines, osteoclastogenesis, and osteolysis, increasing IL-10 production. Metformin also promoted the polarization of macrophages to an anti-inflammatory phenotype in vivo via AMPK activation.
DISCUSSION: A crucial point in limiting and correcting the periprosthetic osteolysis and aseptic loosening is the inhibition of inflammatory factor production and osteoclast activation induced by activated macrophages. The ability of metformin to attenuate osteolysis induced in mouse calvaria by the particles was related to a reduction in osteoclast number and polarization of macrophages to an anti-inflammatory functional phenotype.
CONCLUSIONS: Metformin could limit the osteolysis induced by implant debris. Therefore, we hypothesized that metformin could be a potential drug for osteolysis induced by implant debris.

PMID: 30134793 [PubMed - indexed for MEDLINE]

Identifying genetic markers associated with susceptibility to cardiovascular diseases.

Future Sci OA. 2019 Jan;5(1):FSO350

Authors: Shukla H, Mason JL, Sabyah A

Abstract
The development of cardiovascular diseases (CVDs) is due to a complex interaction between the genome and the environment. Understanding how genetic differences in individuals contribute to their susceptibility to CVDs can help guide practitioners to give the best advice to achieve a favorable outcome for the patient. As genome technologies evolve, genotyping of individuals could be available to all patients using a simple saliva test. Large-scale genome-wide association studies and meta analyses have provided powerful insights into polymorphisms that may be predictive of disease and an individual's response to certain nutrients, but moving forward it is imperative that these insights can be applied in the medical setting to reduce the incidence and mortality of CVDs.

PMID: 30652019 [PubMed]

Coverage rate of ADME genes from commercial sequencing arrays.

Medicine (Baltimore). 2019 Jan;98(3):e13975

Authors: Zaid N, Limami Y, Senhaji N, Errafiy N, Khalki L, Bakri Y, Zaid Y, Amzazi S

Abstract
Pharmacogenomics offers remarkable potential for the rapid translation of discoveries into changes in clinical practice. In the present work, we are interested in evaluating the ability of commercially available genome-wide association sequencing chips to cover genes that have high pharmacogenomics potential.We used a set of 2794 variations within 369 absorption, distribution, metabolism, and elimination (ADME) genes of interest, as previously defined in collaboration with the Pharma ADME consortium. We have compared the Illumina TrueSeq and both Agilent SureSelect and HaloPlex sequencing technologies. We have developed Python scripts to evaluate the coverage for each of these products. In particular, we considered a specific list of 155 allelic variants in 34 genes which present high pharmacogenomics potential. Both the theoretical and practical coverage was assessed.Given the need to have a good coverage to establish confidently the functionality of an enzyme, the observed rates are unlikely to provide sufficient evidence for pharmacogenomics studies. We assessed the coverage using enrichment technology for exome sequencing using the Illumina Trueseq exome, Agilent SureSelectXT1 V4 and V5, and Haloplex exome, which offer a coverage of 96.12%, 91.61%, and 88.38%, respectively.Although pharmacogenomic advances had been limited in the past due in part to the lack of coverage of commercial genotyping chips, it is anticipated that future studies that make use of new sequencing technologies should offer a greater potential for discovery.

PMID: 30653102 [PubMed - in process]

The effect of vitamin D pathway genes and deferasirox pharmacogenetics on liver iron in thalassaemia major patients.

Pharmacogenomics J. 2019 Jan 17;:

Authors: Allegra S, Cusato J, De Francia S, Longo F, Pirro E, Massano D, Avataneo V, De Nicolò A, Piga A, D'Avolio A

Abstract
Monitoring and treating iron overload is crucial in transfusion-dependent thalassaemia patients. Liver stiffness measurement by transient elastography and T2* magnetic resonance imaging represent non-invasive ways to evaluate the adequacy of the iron chelation treatment. We explored the role of single nucleotide polymorphisms involved in vitamin D metabolism, transport and activity, and in deferasirox metabolism on liver iron burden parameters. One-hundred and five beta-thalassaemia patients, treated with deferasirox, have been enrolled. Drug plasma Ctrough and AUC were measured by a HPLC-UV method. Allelic discrimination was performed by real-time PCR. Age, UGT1A1-364 CT/TT and CYP27B1 -1260 GT/TT positively predicted liver stiffness values. Deferasirox dose and serum ferritin negatively predicted T2* data, whereas age and CYP2D6 1457 GG genotype positively influenced these values. The discoveries of this research may be useful for personalized medicine and the proposed method could be applied in patients with hereditary hemochromatosis and myelodysplastic syndromes.

PMID: 30651574 [PubMed - as supplied by publisher]

Prognostic role of genetic polymorphisms of the interleukin-6 signaling pathway in patients with severe heart failure.

Pharmacogenomics J. 2019 Jan 17;:

Authors: Hansen PR, Nelveg-Kristensen KE, Rasmussen HB, Torp-Pedersen C, Køber L, Nielsen CH, Enevold C

Abstract
Heart failure (HF) is associated with perturbations of the interleukin-6 (IL-6) signaling pathway. A total of 559 Danish subjects with severe chronic HF enrolled in the previously reported Echocardiography and Heart Outcome Study were genotyped for three SNPs in IL6, nine in the IL-6 receptor gene (IL6R), and two in the IL-6 signal transducer gene (IL6ST). After a mean follow-up of 5.0 years, 5 SNPs in IL6R introns (rs12083537, rs6684439, rs4845622, rs4537545, and rs7529229) and a SNP in the IL6R coding region (rs2228145, also known as Asp358Ala) were associated with adverse outcomes, e.g., hazard ratios (HRs) for cardiovascular death and all-cause death 1.38 (CI: 1.09-1.76; P = 0.008) and 1.37 (CI: 1.10-1.70; P = 0.004) for rs6684439 heterozygotes, and 1.39 (CI: 1.09-1.77; P = 0.007) and 1.37 (CI: 1.10-1.70; P = 0.005) for rs4845622 heterozygotes, respectively. We conclude that SNPs in the IL-6 signaling pathway may be independent predictors of fatal outcomes in patients with severe HF.

PMID: 30651573 [PubMed - as supplied by publisher]

An update on the safety of prescribing opioids in pediatrics.

Expert Opin Drug Saf. 2019 Jan 16;:

Authors: Parikh JM, Amolenda P, Rutledge J, Szabova A, Chidambaran V

Abstract
INTRODUCTION: The opioid abuse epidemic and its toll on the adolescent population has heightened awareness for safer opioid prescribing practices in pediatric pain management. Opioids remain the mainstay of therapy for severe pain, although there is an emphasis on multimodal therapy. Areas covered: In this update, the authors present information on parenteral/oral opioids commonly used in pediatrics. Recommendations for opioid use in special circumstances including neonates and developmental pharmacokinetic concerns are discussed. Due to noticeable interindividual variability, pharmacogenomics may be important for tailoring pain regimens. In particular, the role of CYP2D6 phenotypes on opioid selection/dosing and clinical implications are discussed. A summary of adverse effects and opioid safety data, and the role of regulations, risk assessment, CDC guidelines, follow up and monitoring for compliance in opioid prescribing, are detailed. Expert opinion: "One size does not fit all" describes the need for public policies focused on pediatric pain and opioid use, as children are not "little adults". Clinical trials to evaluate pharmacokinetic-pharmacodynamics of opioids are currently lacking. Development of novel biased opioid agonists, clinical integration of genetics in informed decision making, and emphasis on top-down approaches to pain management will be key to decrease opioid reliance.

PMID: 30650988 [PubMed - as supplied by publisher]

ME-Class2 reveals context dependent regulatory roles for 5-hydroxymethylcytosine.

Nucleic Acids Res. 2019 Jan 16;:

Authors: Schlosberg CE, Wu DY, Gabel HW, Edwards JR

Abstract
Since the discovery of 5-hydroxymethylcytosine (5hmC) as a prominent DNA modification found in mammalian genomes, an emergent question has been what role this mark plays in gene regulation. 5hmC is hypothesized to function as an intermediate in the demethylation of 5-methylcytosine (5mC) and in the reactivation of silenced promoters and enhancers. Further, weak positive correlations are observed between gene body 5hmC and gene expression. We previously demonstrated that ME-Class is an effective tool to understand relationships between whole-genome bisulfite sequencing data and expression. In this work, we present ME-Class2, a machine-learning based tool to perform integrative 5mCG, 5hmCG and expression analysis. Using ME-Class2 we analyze whole-genome single-base resolution 5mCG and 5hmCG datasets from 20 primary tissue and cell samples to reveal relationships between 5hmCG and expression. Our analysis indicates that conversion of 5mCG to 5hmCG within 2 kb of the transcription start site associates with distinct functions depending on the summed level of 5mCG + 5hmCG. Unchanged levels of 5mCG + 5hmCG (conversion from 5mCG to stable 5hmCG) associate with repression. Meanwhile, decreases in 5mCG + 5hmCG (5hmCG-mediated demethylation) associate with gene activation. Our results demonstrate that ME-Class2 will prove invaluable to interpret genome-wide 5mC and 5hmC datasets and guide mechanistic studies into the function of 5hmCG.

PMID: 30649543 [PubMed - as supplied by publisher]

Precision medicine in childhood asthma.

Curr Opin Allergy Clin Immunol. 2019 Jan 14;:

Authors: Slob EM, Maitland-Van der Zee AH, Koppelman GH, Pijnenburg MW

Abstract
PURPOSE OF REVIEW: Childhood asthma is a heterogeneous disease and many children have uncontrolled disease. Therefore an individualized approach is needed to improve asthma outcomes in children. Precision medicine using clinical characteristics, biomarkers, and the rapidly involving field of genomics and pharmacogenomics aims to achieve asthma control and reduce future risks with less side-effects in individual children with asthma.
RECENT FINDINGS: It is not yet possible to select treatment options on clinical characteristics. Novel monoclonal antibodies are efficacious in patients with severe, eosinophilic asthma. Reduced lung function growth and early decline is a prevalent finding in children with persistent asthma. Pharmacogenetic studies have identified children at risk for cortisol suppression when using inhaled corticosteroids.
SUMMARY: Clinical characteristics and simple biomarkers like eosinophils, IgE, and the fraction of exhaled nitric oxide may be used in clinical practice for a basic precision medicine approach, deciding which children will have the best chance to respond to inhaled corticosteroids and to the biologicals omalizumab and mepolizumab.Further application of pharmacogenomics and breathomics needs additional studies before they can be applied as tools for precision medicine in individual children with asthma.

PMID: 30649013 [PubMed - as supplied by publisher]

"Safety issues of pharmacological acute pain treatment in children".

Clin Pharmacol Ther. 2019 Jan 16;:

Authors: Rodieux F, Piguet V, Desmeules J, Samer CF

Abstract
Acute nociceptive pain management in children is a major public health concern. Effective and safe pain treatment is essential, but safety data cannot be simply extrapolated from adults to children due to pharmacokinetic and pharmacodynamic specificities. In addition, the frequent absence of child-specific data, the difficulty to assess drug tolerability and the infants' inability to communicate properly and voluntarily report adverse drug reactions, make children more vulnerable to safety issues. Awareness of the possible toxicity of analgesics is important but should not lead to suboptimal dosing and underuse of analgesia. A better assessment and individualization of treatment should allow effective prescribing of analgesics in more secure conditions. This article aims to review the safety of acetaminophen, NSAIDs and opioids in children and the precautions that should be taken. This article is protected by copyright. All rights reserved.

PMID: 30648741 [PubMed - as supplied by publisher]

An economic model of the cost-utility of pre-emptive genetic testing to support pharmacotherapy in patients with major depression in primary care.

Pharmacogenomics J. 2019 Jan 16;:

Authors: Sluiter RL, Janzing JGE, van der Wilt GJ, Kievit W, Teichert M

Abstract
The pharmacokinetics of many antidepressants (tricyclic antidepressants (TCA) or selective serotonin re-uptake inhibitors (SSRI)) are influenced by the highly polymorphic CYP2D6 enzyme. Therefore, pharmacogenetics could play an important role in the treatment of depressive patients. The potential cost-utility of screening patients is however still unknown. Therefore, a Markov model was developed to compare the strategy of screening for CYP2D6 and subsequently adjust antidepressant treatment according to a patient's metabolizer profile of poor, extensive, or ultra metabolizer, with the strategy of no screening ('one size fits all' principle). Each week a patient had a probability of side effects, which was followed by dosage titration or treatment switching. After 6 weeks treatment effect was evaluated followed by treatment adjustments if necessary, with a total time horizon of the model of 12 weeks. The analysis was performed from a societal perspective. The strategy of screening compared with no screening resulted in incremental costs of €91 (95 percentiles: €39; €152) more expensive but also more effect with 0.001 quality adjusted life years (QALYs) (95 percentiles: 0.001; 0.002) gain. The incremental cost-effectiveness ratio (ICER) was therefore €77,406 per QALY gained, but varied between €22,500 and €377,500 depending on the price of screening and productivity losses. According to our model, we cannot unequivocally conclude that screening for CYP2D6 in primary care patients using antidepressants is be cost-effective, as the results are surrounded by large uncertainty. Therefore, information from ongoing studies should be used to reduce these uncertainties.

PMID: 30647446 [PubMed - as supplied by publisher]

Warfarin loading dose guided by pharmacogenetics is effective and safe in cardioembolic stroke patients - a randomized, prospective study.

Pharmacogenomics J. 2019 Jan 16;:

Authors: Ruzickova T, Sramek M, Kaplan V, Kumstyrova S, Lacinova Z, Jansky P, Magerova H, Sarbochova I, Schwabova JP, Matoska V, Tomek A

Abstract
Warfarin treatment is commonly started with a fixed loading dose that might be associated with an increased risk of bleeding. An individual maintenance dose can then be estimated based on a pharmacogenetic algorithm. Starting treatment with the estimated dose implies a longer time to reach the therapeutic range. Our goal was to compare the safety and efficacy of initiating warfarin treatment with a loading dose guided by pharmacogenetics versus a maintenance dose. The primary endpoint was time in the therapeutic range (TTR) in the first 10 days of treatment. Secondary endpoints were time to the first international normalized ratio (INR) in therapeutic range (2.0-3.0) and occurrence of serious adverse events. Consenting cardioembolic stroke patients were genotyped for CYP2C9 (cytochrome P450 2C9 gene) and VKORC1 (vitamin K epoxide reductase complex, subunit 1 gene) polymorphisms and a maintenance warfarin dose was estimated. Patients were randomized into two groups. The loading dose group (LDG) patients received twice the estimated dose in the first 2 days of treatment. The maintenance dose group (MDG) patients received the estimated dose directly from day one. The TTR in the first 10 days was significantly higher in the LDG than in the MDG (50.5% vs. 38.3%, p = 0.003). The time to the first INR in this range was significantly shorter in the LDG (5.24 vs. 7.3 days). There were no significant differences in the INR above this range or serious adverse events. Warfarin loading dose guided by pharmacogenetics after recent cardioembolic stroke improved the efficacy of warfarin initiation without increasing the risk of adverse events.

PMID: 30647445 [PubMed - as supplied by publisher]

Cost-effectiveness analysis of pharmacogenomics-guided clopidogrel treatment in Spanish patients undergoing percutaneous coronary intervention.

Pharmacogenomics J. 2019 Jan 16;:

Authors: Fragoulakis V, Bartsakoulia M, Díaz-Villamarín X, Chalikiopoulou K, Kehagia K, Ramos JGS, Martínez-González LJ, Gkotsi M, Katrali E, Skoufas E, Vozikis A, John A, Ali BR, Wordsworth S, Dávila-Fajardo CL, Katsila T, Patrinos GP, Mitropoulou C

Abstract
Clopidogrel is an antiplatelet drug given to patients before and after having a percutaneous coronary intervention (PCI). Genomic variants in the CYP2C19 gene are associated with variable enzyme activities affecting drug metabolism and hence, patients with reduced or increased enzymatic function have increased risk of bleeding. We conducted a cost-effectiveness analysis to compare a pharmacogenomics versus a non-pharmacogenomics-guided clopidogrel treatment for coronary artery syndrome patients undergoing PCI in the Spanish healthcare setting. A total of 549 patients diagnosed with coronary artery disease followed by PCI were recruited. Dual antiplatelet therapy was administrated to all patients from 1 to 12 months after PCI. Patients were classified into two groups: the Retrospective group was treated with clopidogrel based on the clinical routine practice and the Prospective group were initially genotyped for the presence of CYP2C19 variant alleles before treatment with those carrying more than one CYP2C19 variant alleles given prasugrel treatment. We collected data on established clinical and health outcome measures, including, per treatment arm: the percentage of patients that suffered from (a) myocardial infraction, (b) major bleeding and minor bleeding, (c) stroke, (d) the number of hospitalization days, and (e) the number of days patients spent in Intensive Care Unit. Our primary outcome measure for the cost-effectiveness analysis was Quality Adjusted Life Years (QALYs). To estimate the treatment cost for each patient, individual data on its resource used were combined with unit price data, obtained from Spanish national sources. The analysis predicts a survival of 0.9446 QALYs in the pharmacogenomics arm and 0.9379 QALYs in the non-pharmacogenomics arm within a 1-year horizon. The cumulative costs per patient were €2971 and €3205 for the Prospective and Retrospective groups, respectively. The main cost driver of total cost in both arms was hospitalization costs. The incremental cost-effectiveness ratio (ICER) was negative indicating that the PGx was a dominant option. Our data show that pharmacogenomics-guided clopidogrel treatment strategy may represent a cost-effective choice compared with non-pharmacogenomics-guided strategy for patients undergoing PCI.

PMID: 30647444 [PubMed - as supplied by publisher]