Genetic predisposition to atorvastatin-induced myopathy: a case report

What is known and Objective: The major clinical complication of statins is a variety of muscle complaints ranging from myalgia to rhabdomyolysis. There is growing evidence that carriers of genetic polymorphisms in the enzymes and transporters implicated in statin disposition, particularly the SLCO1B1 gene, are at increased risk of myotoxicity. Our objective is to report on two cases of statin-induced myopathy occurring in a family with two patients who are carriers of the loss of function SLCO1B1 genetic variant and to briefly review the related literature. Case summary: Patient 1, a 48-year-old man with history of coronary artery disease, experienced rapidly evolving muscle pain and weakness of the extremities during treatment with atorvastatin 40 mg. Patient 2, a 65-year-old man, father of patient 1, had symptoms similar to those of his son after 2 weeks treatment with the same statin. Atorvastatin was stopped in both cases, and symptoms resolved. On the basis of family relationship between the two patients, it was possible to hypothesize a genetic basis for the myopathy. Genotyping showed the patients to be carriers of the rs4363657 polymorphism of SLCO1B1 gene. What is new and Conclusion: The two cases reported here and the brief literature review emphasize the impact of genetic factors on the risk of myopathy with statins. Although genotyping all patients before initiating therapy is not recommended at present, pharmacogenetic testing may be useful for new patients who have a family history of statin-induced myopathy

Left atrial appendage occlusion in patients with atrial fibrillation and large prevalence of prior intracranial bleeding

Abstract Background: Left atrial appendage occlusion (LAAO) represents an alternative approach for the prevention of cardioembolic stroke in patients with nonvalvular atrial fibrillation (NVAF) and contraindication for oral anticoagulation (OAC). The aim of our study was to analyse the outcomes in patients treated with LAAO, with a focus on cases with previous intracranial bleeding. Methods: Sixty patients with NVAF underwent LAAO (75.4 ± 9 years); mean CHA2DS2-VASc was 4.4 ± 1.7, mean HAS-BLED 3.2 ± 0.9. Thirty-two patients (53.3%) reported previous intracranial bleeding. Ischaemic and bleeding events recorded during follow-up were compared with expected event rates according to CHA2DS2-VASc and HAS-BLED scores. Results: Device implantation was successful in 58 patients (96.7%). The antiplatelet therapy was tailored according to patients' bleeding risk. During follow-up (2.32 ± 1.5 years) 3 ischaemic strokes and 1 transient ischaemic attack occurred, versus 13 total expected thromboembolic events (P = 0.033); 5 major bleedings were observed, versus 7 expected ones, if the patients were under OAC. Considering the combined endpoint (thromboembolic and major bleeding events) 9 events were observed versus 20 expected major events (P = 0.031). In the prespecified subgroup of patients with previous intracranial bleeding, two ischaemic strokes and one transient ischaemic attack were observed during follow-up versus six total expected thromboembolic events; no intracranial bleeding recurrence was recorded. Regarding the combined endpoint four major events were recorded versus nine expected ones. Conclusion: LAAO is an efficient and safe option for the prevention of cardioembolic stroke in patients with NVAF, high thromboembolic risk and contraindication to OAC, particularly in patients with previous intracranial bleeding

61. Rapid and portable, lab-on-chip, point-of-care genotyping for evaluating clopidogrel metabolism

Background: Dual antiplatelet therapy with aspirin and a platelet P2Y12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor) is a cornerstone of antithrombotic treatment in patients with acute coronary syndromes (ACS). Clopidogrel has been the standard of care for nearly a decade; however, its clinical efficacy is influenced by a considerable inter-patient variability in response, clearly associated to cytochrome P (CYP) enzyme genetic variations. We used a novel point-of-care lab-on-chip instrument to genotype ACS patients in order to identify carriers of the ATB-binding cassette ABCB1 3435, CYP2C19*2 and CYPC2C19*17 alleles and adjust the pharmacological approach accordingly. Methods and results: Between October 2012 and January 2013, 160 ACS patients were enrolled at the Cardiology Unit of the Ospedale Niguarda Ca Granda and genotyped at the patients' point-of-care using the newly developed Q3 portable real-time PCR instrument which remarkably scored the CYP2C19*2, CYP2C19*17, and ABCB13435 alleles in a time of 70 min from DNA extraction to final genotype calls; concordance with the other gold-standard genotyping techniques was 100%. Conclusions: The Q3 instrument proved to be as reliable as the current conventional techniques. As genotyping in the ACS setting cannot be delegated to centralised clinical laboratories for reasons of time, genotyping at the patients' bedside provides an opportunity to conduct large-scale randomised trials in order to assess whether adding genotype data to clinical variables improves clinical outcomes. (C) 2015 Elsevier B.V. All rights reserved

Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes: The PHARMCLO Trial

Background: Although clopidogrel is still frequently used in patients with acute coronary syndromes (ACS), its efficacy is hampered by interpatient response variability caused by genetic polymorphisms associated with clopidogrel's metabolism. Objectives: The goal of this study was to evaluate whether selecting antiplatelet therapy (clopidogrel, prasugrel, or ticagrelor) on the basis of a patient's genetic and clinical characteristics leads to better clinical outcomes compared with the standard of care, which bases the selection on clinical characteristics alone. Methods: Patients hospitalized for ACS were randomly assigned to standard of care or the pharmacogenomic arm, which included the genotyping of ABCB1, CYP2C19*2, and CYP2C19*17 using an ST Q3 system that provides data within 70 min at each patient's bedside. The patients were followed up for 12 ± 1 month for the primary composite endpoint of cardiovascular death and the first occurrence of nonfatal myocardial infarction, nonfatal stroke, and major bleeding defined according to Bleeding Academic Research Consortium type 3 to 5 criteria. Results: After enrolling 888 patients, the study was prematurely stopped. Clopidogrel was used more frequently in the standard-of-care arm (50.7% vs. 43.3%), ticagrelor in the pharmacogenomic arm (42.6% vs. 32.7%; p = 0.02), and prasugrel was equally used in both arms. The primary endpoint occurred in 71 patients (15.9%) in the pharmacogenomic arm and in 114 (25.9%) in the standard-of-care arm (hazard ratio: 0.58; 95% confidence interval: 0.43 to 0.78; p < 0.001). Conclusions: A personalized approach to selecting antiplatelet therapy for patients with ACS may reduce ischemic and bleeding events. (Pharmacogenetics of Clopidogrel in Patients With Acute Coronary Syndromes [PHARMCLO]; NCT03347435

International Social Survey Programme: Work Orientations II - ISSP 1997

The International Social Survey Programme (ISSP) is a continuous programme of cross-national collaboration running annual surveys on topics important for the social sciences. The programme started in 1984 with four founding members - Australia, Germany, Great Britain, and the United States – and has now grown to almost 50 member countries from all over the world. As the surveys are designed for replication, they can be used for both, cross-national and cross-time comparisons. Each ISSP module focuses on a specific topic, which is repeated in regular time intervals. Please, consult the documentation for details on how the national ISSP surveys are fielded. The present study focuses on questions about work, employment and work orientations.Desired distribution of time for selected activities such as work, leisure time usw.; work orientation (scale); carrying out work in household; importance of selected demands of a job; most important criteria for determination of amount of salary; influence of new technologies on job offerings and on quality of job; preference for work in service area or industry as well as in private economy or public sector; preference for employee status or occupational self-employment as well as for working in a large concern or in a small company; part-time employment; interest in full-time work; expected difficulties in looking for a job; payment of work; description of personal commitment to work; preference for more work and more pay or for more leisure time; certainty of one´s own job; significance of career opportunities and structuring of flexible working hours; characterization of work as hard physical activity and description of the extent of stress on the job; physical exhaustion after work; dangerous and unhealthful job situations; personal opportunity to influence the structuring of the work day or work processes; general job description; benefit of skills learned during time in school or university; judgement on the relationship between management and employees; atmosphere at work; work satisfaction; absence in the last 6 months; search for new job in the next 12 months. Those not employed were asked: work for more than one year and time of end of last paid job; reasons for the end of employment; expected difficulties in the job search; current search for work; manner of search for work; primary income source. Demography: sex; age; marital status; living together with a partner; education and duration of education; current employment status; employment in private or public sector; self-employment or employee; personal employees; time worked each week; superior function and span of control; company size; income; religious denomination; religiousness; union member; self-assessment of social class; self-assessment on a left-right continuum; party preference; size of household and composition; city size; region; original country of origin or ethnic group affiliation.Das International Social Survey Programme (ISSP) ist ein länderübergreifendes, fortlaufendes Umfrageprogramm, das jährlich Erhebungen zu Themen durchführt, die für die Sozialwissenschaften wichtig sind. Das Programm begann 1984 mit vier Gründungsmitgliedern - Australien, Deutschland, Großbritannien und den Vereinigten Staaten - und ist inzwischen auf fast 50 Mitgliedsländer aus aller Welt angewachsen. Da die Umfragen auf Replikationen ausgelegt sind, können die Daten sowohl für länder- als auch für zeitübergreifende Vergleiche genutzt werden. Jedes ISSP-Modul konzentriert sich auf ein bestimmtes Thema, das in regelmäßigen Zeitabständen wiederholt wird. Details zur Durchführung der nationalen ISSP-Umfragen entnehmen Sie bitte der Dokumentation. Die vorliegende Studie konzentriert sich auf Fragen zur Arbeit, Beschäftigungsverhältnissen und Arbeitsorientierungen.Gewünschte Zeitaufteilung für ausgewählte Tätigkeiten wie Arbeit, Freizeit usw.; Arbeitsorientierung (Skala); Erledigung von Arbeiten im Haushalt; Wichtigkeit ausgewählter Ansprüche an einen Arbeitsplatz; wichtigste Kriterien für die Bestimmung der Gehaltshöhe; Einfluß neuer Technologien auf Arbeitsplatzangebot und auf Arbeitsplatzqualität; Präferenz für die Arbeit im Dienstleistungsbereich oder in der Industrie sowie in der Privatwirtschaft oder im öffentlichen Sektor; Präferenz für Arbeitsnehmerstatus oder berufliche Selbständigkeit sowie für das Arbeiten in einem Großunternehmen oder in einem kleinen Unternehmen; Teilzeitbeschäftigung; Interesse an einer Vollzeitbeschäftigung; erwartete Schwierigkeiten bei einer Jobsuche; Bezahlung der Arbeit; Beschreibung des eigenen Engagements bei der Arbeit; Präferenz für mehr Arbeit und mehr Lohn oder für mehr Freizeit; Sicherheit des eigenen Arbeitsplatzes; Bedeutung von Karrieremöglichkeiten und flexibler Arbeitszeitgestaltung; Charakterisierung der Arbeit als harte physische Tätigkeit und Beschreibung des Ausmaßes von Streß bei der Arbeit; physische Erschöpfung nach der Arbeit; gefährliche und ungesunde Arbeitsplatzsituationen; eigene Einflußmöglichkeit auf die Gestaltung des Arbeitstages bzw. der Arbeitsabläufe; allgemeine Arbeitsplatzbeschreibung; Nutzen der erlernten Fähigkeiten aus der Schul- oder Universitätszeit; Beurteilung des Verhältnisses zwischen Management und Mitarbeitern; Betriebsklima; Arbeitszufriedenheit; Abwesenheit in den letzten 6 Monaten; Suche nach neuer Arbeit in den nächsten 12 Monaten. Nichterwerbstätige wurden gefragt: Arbeit für mehr als ein Jahr und Zeitpunkt des Endes der letzten bezahlten Arbeit; Gründe für das Ende der Beschäftigung; erwartete Schwierigkeiten bei der Jobsuche; momentane Suche nach Arbeit; Art der Arbeitssuche; Haupteinkommensquelle. Demographie: Geschlecht; Alter; Familienstand; Zusammenleben mit einem Partner; Ausbildung und Ausbildungsdauer; momentaner Beschäftigungsstatus; Beschäftigung im privaten oder öffentlichen Sektor; Selbständigkeit bzw. Arbeitsverhältnis; eigene Angestellte; Wochenarbeitszeit; Vorgesetztenfunktion und Kontrollspanne; Betriebsgröße; Einkommen; Konfession; Religiosität; Gewerkschaftsmitglied; Selbsteinschätzung der Schichtzugehörigkeit; Selbsteinschätzung auf einem Links-Rechts-Kontinuum; Parteipräferenz; Haushaltsgröße und Zusammensetzung; Ortsgröße; Region; ursprüngliches Herkunftsland bzw. ethnische Gruppenzugehörigkeit