Adverse drug reactions associated with amitriptyline - protocol for a systematic multiple-indication review and meta-analysis

Background: Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-thecounter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals. Methods: A systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including <100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using metaregression (for indication, outcome, and time points) and I2 statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment. Discussion: We will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations

Health-related preferences of older patients with multimorbidity: the protocol for an evidence map

Introduction: Interaction of conditions and treatments, complicated care needs and substantial treatment burden make patient–physician encounters involving multimorbid older patients highly complex. To optimally integrate patients’ preferences, define and prioritise realistic treatment goals and individualise care, a patient-centred approach is recommended. However, the preferences of older patients, who are especially vulnerable and frequently multimorbid, have not been systematically investigated with regard to their health status. The purpose of this evidence map is to explore current research addressing health-related preferences of older patients with multimorbidity, and to identify the knowledge clusters and research gaps. Methods and analysis: To identify relevant research, we will conduct searches in the electronic databases MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL, Social Science Citation Index, Social Science Citation Index Expanded and the Cochrane library from their inception. We will check reference lists of relevant articles and carry out cited reference research (forward citation tracking). Two independent reviewers will screen titles and abstracts, check full texts for eligibility and extract the data. Any disagreement will be resolved and consensus reached with the help of a third reviewer. We will include both qualitative and quantitative studies, and address preferences from the patients’ perspectives in a multimorbid population of 60 years or older. There will be no restrictions on the publication language. Data extraction tables will present study and patient characteristics, aim of study, methods used to identify preferences and outcomes (ie, type of preferences). We will summarise the data using tables and figures (ie, bubble plot) to present the research landscape and to describe clusters and gaps. Ethics and dissemination: Due to the nature of the proposed evidence map, ethics approval will not be required. Results from our research will be disseminated by means of specifically prepared materials for patients, at relevant (inter)national conferences and via publication in peer-reviewed journals

Association between antenatal glucocorticoid exposure and the activity of the stress system, cognition, and behavior in 8‐ to 9‐year‐old children: A prospective observational study

Introduction Glucocorticoid (GC) ‐induced fetal programming of the activity of the hypothalamus–pituitary–adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood. Material and methods Prospective observational study in 31 children whose mothers received single ( n = 19) or multiple ( n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+ 6 weeks of gestation) compared with 38 non‐exposed, age‐matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention‐deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG). Results There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM‐exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high‐frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM‐exposed children had lower IQ scores than the unexposed group. BM‐exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose–response relation between BM exposure and activity of the ANS and IQ was estimated in post‐hoc analyses. Conclusions Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life‐saving therapy, but its prescription may warrant a well‐balanced risk–benefit assessment

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy: Study protocol of a cluster randomized clinical trial (Multi-PAP project)

Background: Multimorbidity is associated with negative effects both on people''s health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (=3 chronic diseases) and polypharmacy (=5 drugs prescribed in =3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT0286679

Temporal and spatial analysis of the 2014-2015 Ebola virus outbreak in West Africa

West Africa is currently witnessing the most extensive Ebola virus (EBOV) outbreak so far recorded. Until now, there have been 27,013 reported cases and 11,134 deaths. The origin of the virus is thought to have been a zoonotic transmission from a bat to a two-year-old boy in December 2013 (ref. 2). From this index case the virus was spread by human-to-human contact throughout Guinea, Sierra Leone and Liberia. However, the origin of the particular virus in each country and time of transmission is not known and currently relies on epidemiological analysis, which may be unreliable owing to the difficulties of obtaining patient information. Here we trace the genetic evolution of EBOV in the current outbreak that has resulted in multiple lineages. Deep sequencing of 179 patient samples processed by the European Mobile Laboratory, the first diagnostics unit to be deployed to the epicentre of the outbreak in Guinea, reveals an epidemiological and evolutionary history of the epidemic from March 2014 to January 2015. Analysis of EBOV genome evolution has also benefited from a similar sequencing effort of patient samples from Sierra Leone. Our results confirm that the EBOV from Guinea moved into Sierra Leone, most likely in April or early May. The viruses of the Guinea/Sierra Leone lineage mixed around June/July 2014. Viral sequences covering August, September and October 2014 indicate that this lineage evolved independently within Guinea. These data can be used in conjunction with epidemiological information to test retrospectively the effectiveness of control measures, and provides an unprecedented window into the evolution of an ongoing viral haemorrhagic fever outbreak.status: publishe

Recommendations for the primary prevention of atherosclerotic cardiovascular disease in primary care: study protocol for a systematic guideline review

Schürmann L, Bredehorst M, González González AI, et al. Recommendations for the primary prevention of atherosclerotic cardiovascular disease in primary care: study protocol for a systematic guideline review. BMJ Open. 2023;13(12): e074788.INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) was the main cause of death in Germany in 2021, with major risk factors (ie, hypertension, diabetes, dyslipidaemia, obesity and certain lifestyle factors) being highly prevalent. Preventing ASCVD by assessment and modification of these risk factors is an important challenge for general practitioners. This study aims to systematically review and synthesise recent recommendations of national and international guidelines regarding the primary prevention of ASCVD in adults in primary care.; METHODS AND ANALYSIS: We will conduct a systematic review of clinical practice guidelines (CPGs) to evaluate primary prevention strategies for ASCVD. CPGs will be retrieved from MEDLINE and the Turning Research Into Practice database, guideline-specific databases and websites of guidelines-producing societies, with searches limited to publications from 2016 onwards. We will include CPGs in English, Spanish, German or Dutch languages that provide evidence-based recommendations for ASCVD prevention. The study population will include adults without diagnosed ASCVD. Two independent reviewers will assess guideline eligibility and quality by means of the mini-checklist MiChe, and extract study characteristics and relevant recommendations for further consistency analysis. A third reviewer will resolve disagreements. Findings will be presented as a narrative synthesis and in tabular form.; ETHICS AND DISSEMINATION: This review does not require ethical approval. Our systematic review will inform the CPG of the German College of General Practitioners and Family Physicians on the primary prevention of ASCVD. The review results will also be disseminated through publications in peer-reviewed journals and presentations at local, national and international conferences.; PROSPERO REGISTRATION NUMBER: CRD42023394605. © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ

Stakeholder Perspectives on the Development and Implementation of a Polypharmacy Management Program in Germany: Results of a Qualitative Study

Structured management programs have been developed for single diseases but rarely for patients with multiple medications. We conducted a qualitative study to investigate the views of stakeholders on the development and implementation of a polypharmacy management program in Germany. Overall, we interviewed ten experts in the fields of health policy and clinical practice. Using content analysis, we identified inclusion criteria for the selection of suitable patients, the individual elements that should make up such a program, healthcare providers and stakeholders that should be involved, and factors that may support or hinder the program’s implementation. All stakeholders were well aware of polypharmacy-related risks and challenges, as well as the urgent need for change. Intervention strategies should address all levels of care and include all concerned patients, caregivers, healthcare providers and stakeholders, and involved parties should agree on a joint approach.</jats:p

Impact of antenatal glucocorticoid exposure on the activity of the stress system, cognition and behavior in 8 to 9-year-old children: a clinical cohort study

Objective: To determine stress-sensitivity and neurodevelopmental outcome in 8- to 9-year-old children following antenatal exposure to glucocorticoid (GC) prophylaxis for neonatal respiratory distress syndrome. Design: Clinical cohort study. Setting: University-based obstetric clinic in Central Germany. Population: 31 term or near-term born children whose mothers received single or multiple courses of betamethasone (BM) to induce fetal lung maturation in threatened preterm birth compared to 39 non-exposed children. Methods: Multi-system assessment of the individual stress response together with an analysis of cognitive, behavioral and electrocortical functioning. Main Outcome Measures: Activity of the hypothalamus-pituitary-adrenal axis (HPAA, primary outcome domain) and the autonomic nervous system (ANS, secondary outcome domain) including markers of heart rate variability (HRV). Additional endpoints were the cognitive performance (IQ) and attention-deficit/hyperactivity disorder (ADHD) core symptoms. Results: HPAA activity was not affected by antenatal GC-exposure. ANS activity in GC-exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high-frequency band power of HRV (1313 vs. 762 msec2/Hz, p=0.03). BM-exposed children had lower cognitive performance (IQ 96.9 vs. 108.0, p&lt;0.01) and a marginally higher ADHD score (FBB-ADHD scale 5.5 vs. 4.6 points, p=0.04). A monotonic dose-response relationship between GC-exposure and stress-induced activity of the ANS and IQ was estimated post-hoc. Conclusions: Antenatal exposure to supraphysiological concentrations of BM in the context of threatened preterm birth was associated with multidimensional changes in stress-sensitivity and neurodevelopment in later life. As these changes may be dose-dependent, antenatal GC prophylaxis should be used at the minimum effective dose after a careful risk-benefit assessment.</jats:p

Multimorbilidad en medicina de familia y los principios Ariadne : un enfoque centrado en la persona

La multimorbilidad, definida como la presencia de dos o más enfermedades crónicas en un mismo individuo, conlleva consecuencias negativas para la persona e importantes retos para los sistemas sanitarios. En atención primaria, donde recae esencialmente la atención de este grupo de pacientes, la consulta es más compleja que la de un paciente con una única enfermedad debido, entre otros, al hecho de tener que manejar mayor cantidad de información clínica, disponer de poca evidencia científica para abordar la multimorbilidad, y tener que coordinar la labor de múltiples profesionales para garantizar la continuidad asistencial. Además, para poder implementar correctamente los planes de tratamiento en estos pacientes es necesario un proceso de toma de decisiones compartida médico-paciente. Entre las distintas herramientas disponibles para apoyar dicho proceso, recientemente se ha desarrollado una dirigida específicamente a pacientes con multimorbilidad en atención primaria y que se describe en el presente artículo: los principios Ariadne.Multimorbidity, defined as the coexistence of two or more chronic conditions in one same individual, has negative consequences for people suffering from it and it poses a real challenge for health systems. In primary care, where most of these patients are attended, the clinical management of multimorbidity can be a complex task due, among others, to the high volume of clinical information that needs to be handled, the scarce scientific evidence available to approach multimorbidity, and the need for coordination among multiple health providers to guarantee continuity of care. Moreover, the adequate implementation of the care plan in these patients requires a process of shared decision making between patient and physician. One of the available tools to support this process, which is specifically directed to patients with multimorbidity in primary care, is described in the present article: the Ariadne principles

MULTIPAP Study: Improving healthcare for patients with multimorbidity

BackgroundThe steady rise in multimorbidity entails serious consequences for our populations, challenges healthcare systems, and calls for specific clinical approaches of proven effectiveness. The MULTIPAP Study comprises three sequential projects (MULTIPAP and MULTIPAP Plus RCTs, and the MULTIPAP Cohort). Results of MULTIPAP RCT are presented.AimTo evaluate the effectiveness of a complex, patient-centred intervention in young-old patients with multimorbidity and polypharmacy.MethodPragmatic cluster-randomised clinical trial in a primary healthcare setting. GPs were randomly allocated to either conventional care or the MULTIPAP intervention based on the Ariadne Principles with two components: GPs e-training (that is, eMULTIPAP addresses specific, key concepts on multimorbidity, polypharmacy and shared decision-making) and GP–patient-centred interview. Young-old patients aged 65–74 years with multimorbidity and polypharmacy were included. Main outcome: difference in the Medication Appropriateness Index (MAI) after 6-month follow-up between groups. Secondary outcomes: MAI, quality of life, patient perception, health services use, treatment adherence and cost-effectiveness after 12-month follow-up.Results117 GPs from 38 Spanish primary health care recruited 593 patients randomly assigned to the intervention/control groups. Difference in MAI scores between groups in the intention-to-treat analysis after 6 months’ follow-up: −2.42 (−4.27 to −0.59), P = 0.009 (adjusted difference in mean MAI score −1.81(−3.35 to −0.27), P = 0.021). Secondary outcomes: not significant, including quality of life (adjusted difference in mean EQ-5D-5L (VAS) 2.94 (−1.39 to 7.28), P = 0.183, EQ-5D-5L (index) −0.006(−0.034 to 0.022), P = 0.689).ConclusionThe intervention significantly improved medication appropriateness. The observed quality of life improvement was not significant. GPs e-training in multimorbidity has shown to be feasible and well accepted by the professionals. Future studies may test whether this format facilitates implementation.</jats:sec