Harm effects in non-registered versus registered randomized controlled trials of medications: a retrospective cohort study of clinical trials.

BACKGROUND: Trial registration aims to address potential bias from selective or non-reporting of findings, and therefore has a vital role in promoting transparency and accountability of clinical research. In this study, we aim to investigate the influence of trial registration on estimated harm effects in randomized controlled trials of medication interventions. METHODS: We searched PubMed for systematic reviews and meta-analyses of randomized trials on medication harms indexed between January 1, 2015, and January 1, 2020. To be included in the analyses, eligible meta-analyses should have at least five randomized trials with distinct registration statuses (i.e., prospectively registered, retrospectively registered, and non-registered) and 2 by 2 table data for adverse events for each trial. To control for potential confounding, trials in each meta-analysis were analyzed within confounder-harmonized groups (e.g., dosage) identified using the Directed Acyclic Graph method. The harm estimates arising from the trials with different registration statuses were compared within the confounder-harmonized groups using hierarchical linear regression. Results are shown as ratio of odds ratio (OR) and 95% confidence interval (CI). RESULTS: The dataset consists of 629 meta-analyses of harms with 10,069 trials. Of these trials, 74.3% were registered, and 23.9% were not registered, and for those registered, 70.6% were prospectively registered, while 26.3% were retrospectively registered. In comparison to prospectively registered trials, both non-registered trials (ratio of OR = 0.82, 95%CI 0.68 to 0.98, P = 0.03) and retrospectively registered trials (ratio of OR = 0.75, 95%CI 0.66 to 0.86, P < 0.01) had lower OR for harms based on 69 and 126 confounders-harmonized groups. The OR of harms did not differ between retrospectively registered and non-registered trials (ratio of OR = 1.02, 95%CI 0.85 to 1.23, P = 0.83) based on 76 confounders-harmonized groups. CONCLUSIONS: Medication-related harms may be understated in non-registered trials, and there was no obvious evidence that retrospective registration had a demonstrable benefit in reducing such selective or absent reporting. Prospective registration is highly recommended for future trials.

Influence of lack of blinding on the estimation of medication-related harms: a retrospective cohort study of randomized controlled trials.

BACKGROUND: Empirical evidence suggests that lack of blinding may be associated with biased estimates of treatment benefit in randomized controlled trials, but the influence on medication-related harms is not well-recognized. We aimed to investigate the association between blinding and clinical trial estimates of medication-related harms. METHODS: We searched PubMed from January 1, 2015, till January 1, 2020, for systematic reviews with meta-analyses of medication-related harms. Eligible meta-analyses must have contained trials both with and without blinding. Potential covariates that may confound effect estimates were addressed by restricting trials within the comparison or by hierarchical analysis of harmonized groups of meta-analyses (therefore harmonizing drug type, control, dosage, and registration status) across eligible meta-analyses. The weighted hierarchical linear regression was then used to estimate the differences in harm estimates (odds ratio, OR) between trials that lacked blinding and those that were blinded. The results were reported as the ratio of OR (ROR) with its 95% confidence interval (CI). RESULTS: We identified 629 meta-analyses of harms with 10,069 trials. We estimated a weighted average ROR of 0.68 (95% CI: 0.53 to 0.88, P < 0.01) among 82 trials in 20 meta-analyses where blinding of participants was lacking. With regard to lack of blinding of healthcare providers or outcomes assessors, the RORs were 0.68 (95% CI: 0.53 to 0.87, P < 0.01 from 81 trials in 22 meta-analyses) and 1.00 (95% CI: 0.94 to 1.07, P = 0.94 from 858 trials among 155 meta-analyses) respectively. Sensitivity analyses indicate that these findings are applicable to both objective and subjective outcomes. CONCLUSIONS: Lack of blinding of participants and health care providers in randomized controlled trials may underestimate medication-related harms. Adequate blinding in randomized trials, when feasible, may help safeguard against potential bias in estimating the effects of harms.

What really is nontokenistic fully inclusive patient and public involvement/engagement in research?

Patient and public involvement and engagement (PPIE) is critically important in healthcare research. A useful starting point for researchers to understand the scope of PPIE is to review the definition from the National Institute for Health and Care Research (NIHR) as, 'research being carried out "with" or "by" members of the public rather than "to", "about" or "for" them'. PPIE does not refer to participation in research, but to actively shaping its direction. The 'Effectiveness of a decision support tool to optimise community-based tailored management of sleep for people living with dementia or mild cognitive impairment (TIMES)' study is funded through the NIHR programme grant for applied research. TIMES has thoroughly embraced PPIE by ensuring the person's voice is heard, understood, and valued. This editorial showcases how the TIMES project maximised inclusivity, and we share our experiences and top tips for other researchers. We base our reflections on the six key UK standards for public involvement; Inclusive Opportunities, Working Together, Support and Learning, Communications, Impact and Governance. We present our work, which had been co-led by our PPIE leads, academics and partners including, together in dementia everyday, Innovations in Dementia, The UK Network of Dementia Voices (Dementia Engagement & Empowerment Project) and Liverpool Chinese Wellbeing. We have a Lived Experience Advisory Forum on Sleep, which includes people with dementia, family carers, representatives of the South Asian Community and the Chinese community.

Changes in exhaled volatile organic compounds following indirect bronchial challenge in suspected asthma.

BACKGROUND: Inhaled mannitol provokes bronchoconstriction via mediators released during osmotic degranulation of inflammatory cells, and, hence represents a useful diagnostic test for asthma and model for acute attacks. We hypothesised that the mannitol challenge would trigger changes in exhaled volatile organic compounds (VOCs), generating both candidate biomarkers and novel insights into their origin. METHODS: Participants with a clinical diagnosis of asthma, or undergoing investigation for suspected asthma, were recruited. Inhaled mannitol challenges were performed, followed by a sham challenge after 2 weeks in participants with bronchial hyper-responsiveness (BHR). VOCs were collected before and after challenges and analysed using gas chromatography-mass spectrometry. RESULTS: Forty-six patients (mean (SD) age 52 (16) years) completed a mannitol challenge, of which 16 (35%) were positive, and 15 of these completed a sham challenge. Quantities of 16 of 51 identified VOCs changed following mannitol challenge (p<0.05), of which 11 contributed to a multivariate sparse partial least square discriminative analysis model, with a classification error rate of 13.8%. Five of these 16 VOCs also changed (p<0.05) in quantity following the sham challenge, along with four further VOCs. In patients with BHR to mannitol distinct postchallenge VOC signatures were observed compared with post-sham challenge. CONCLUSION: Inhalation of mannitol was associated with changes in breath VOCs, and in people with BHR resulted in a distinct exhaled breath profile when compared with a sham challenge. These differentially expressed VOCs are likely associated with acute airway inflammation and/or bronchoconstriction and merit further investigation as potential biomarkers in asthma.

EVALUATION OF THE FIRST OLDER PEOPLE'S EMERGENCY DEPARTMENT IN ENGLAND - A RETROSPECTIVE COHORT STUDY.

BACKGROUND: The complexity of older patients along with trends in poorer outcomes in the emergency department (ED) has prompted research into how EDs can adapt to meet the needs of an aging population. A separate Older People's Emergency Department (OPED) has been proposed to improve care at the front door. OBJECTIVE: Compare patient flow in a dedicated OPED at a University Hospital in Norfolk, United Kingdom, against that of the main ED. METHODS: We carried out a retrospective cohort study to compare older patients attending the ED in 2019 against those attending the newly formed OPED service in 2020. Multivariable logistic regression was performed to estimate adjusted odds ratios (emergency admissions, meeting England's 4-h national target, re-admissions, all-cause 30-day mortality, clinical frailty screening, and discharge to original place of residence). RESULTS: Clinical assessment in the OPED did not significantly lower the proportion of patients admitted to the hospital (adjusted odds ratio 0.84; 95% confidence interval 0.61-1.16).  There were significant reductions in overall time spent in the department, time to initial clinician review, and time to frailty screening. Patients seen in the OPED were more likely to meet the national 4-h target and more likely to be discharged to their original place of residence. CONCLUSIONS: Assessment in the OPED was not associated with a significantly reduced likelihood of hospitalization. However, patients had a shorter wait for clinical assessment, with concomitant reduction in department length of stay.

A review of trial and real-world data applying elements of a realist approach to identify behavioural mechanisms supporting practitioners to taper opioids.

This evidence synthesis applying realist concepts and behavioural science aimed to identify behavioural mechanisms and contexts that facilitate prescribers tapering opioids. We identified relevant opioid-tapering interventions and services from a 2018 international systematic review and a 2019 England-wide survey, respectively. Interventions and services were eligible if they provided information about contexts and/or behavioural mechanisms influencing opioid-tapering success. A stakeholder group (n = 23) generated draft programme theories based around the 14 domains of the Theoretical Domains Framework. We refined these using the trial and service data. From 71 articles and 21 survey responses, 56 and 16 respectively were included, representing primary care, hospital, specialist pain facilities and prison services. We identified 6 programme theories comprising 5 behavioural mechanisms: prescribers' knowledge about how to taper; build prescribers' beliefs about capabilities to initiate tapering discussions and manage psychological consequences of tapering; perceived professional role in tapering; the environmental context enabling referral to specialists; and facilitating positive social influence by aligning patient: prescriber expectations of tapering. No interventions are addressing all 6 mechanisms supportive of tapering. Work is required to operationalise programme theories according to organisational structures and resources. An example operationalisation is combining tapering guidelines with information about local excess opioid problems and endorsing these with organisational branding. Prescribers being given the skills and confidence to initiate tapering discussions by training them in cognitive-based interventions and incorporating access to psychological and physical support in the patient pathway. Patients being provided with leaflets about the tapering process and informed about the patient pathway.

Urinary Leukotriene E4 as a Biomarker in NSAID-Exacerbated Respiratory Disease (N-ERD): a Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Non-steroidal exacerbated respiratory disease (N-ERD) currently requires aspirin challenge testing for diagnosis. Urinary leukotriene E4 (uLTE4) has been extensively investigated as potential biomarker in N-ERD. We aimed to assess the usefulness of uLTE4 as a biomarker in the diagnosis of N-ERD. RECENT FINDINGS: N-ERD, formerly known as aspirin-intolerant asthma (AIA), is characterised by increased leukotriene production. uLTE4 indicates cysteinyl leukotriene production, and a potential biomarker in N-ERD. Although several studies and have examined the relationship between uLTE4 and N-ERD, the usefulness of uLTE4 as a biomarker in a clinical setting remains unclear. FINDINGS: Our literature search identified 38 unique eligible studies, 35 were included in the meta-analysis. Meta-analysis was performed (i.e. pooled standardised mean difference (SMD) with 95% confidence intervals (95% CI)) and risk of bias assessed (implementing Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (Cochrane DTA)). Data from 3376 subjects was analysed (1354 N-ERD, 1420 ATA, and 602 HC). uLTE4 was higher in N-ERD vs ATA (n = 35, SMD 0.80; 95% CI 0.72-0.89). uLTE4 increased following aspirin challenge in N-ERD (n = 12, SMD 0.56; 95% CI 0.26-0.85) but not ATA (n = 8, SMD 0.12; CI - 0.08-0.33). This systematic review and meta-analysis showed that uLTE4 is higher in N-ERD than ATA or HC. Likewise, people with N-ERD have greater increases in uLTE4 following aspirin challenge. However, due to the varied uLTE4 measurement and result reporting practice, clinical utility of these findings is limited. Future studies should be standardised to increase clinical significance and interpretability of the results.

Cognitive decline associated with anticholinergics, benzodiazepines and Z-drugs: Findings from The Irish Longitudinal Study on Ageing (TILDA).

AIMS: To estimate the association between patterns of anticholinergic, benzodiazepine and Z-drug medication use and change in cognitive function in middle-aged and older adults. METHODS: This prospective cohort study used data from the first three waves of The Irish Longitudinal Study on Ageing (TILDA), including community-dwelling adults aged ≥50 years followed for up to 4 years (n = 7027). Cognitive function was assessed using the Mini Mental State Examination, animal naming test and word recall tests. Regular medication use was self-reported at baseline and follow-up interviews at 2 and 4 years. Pharmacy dispensing claims for a subset (n = 2905) allowed assessment of medication use between interviews and cumulative dosage. Medication use at consecutive waves of TILDA was analysed in relation to change in cognitive function between waves. RESULTS: Strongly anticholinergic medications (Anticholinergic Cognitive Burden scale 3), benzodiazepines and Z-drugs were reported by 7.3%, 5.8% and 5.1% of participants, respectively, at any time during the study. Adjusting for potential confounders, new anticholinergic use between interviews was associated with change in recall score (-1.09, 95% confidence interval -1.64, -0.53) over 2 years compared to non-use, but not with MMSE (0.07; 95% CI -0.21, 0.34) or animal naming (-0.70; 95% CI -1.43, 0.03). The pharmacy claims analysis was consistent with this finding. Other hypothesised associations were not supported. CONCLUSIONS: Except for new use of anticholinergic medications, no other findings supported a risk of cognitive decline over 2-year periods in this middle-aged and older cohort. Patients and prescribers should weigh this potential risk against potential benefits of commencing anticholinergic medications.

Calcium intake, calcium supplementation and cardiovascular disease and mortality in the British population: EPIC-norfolk prospective cohort study and meta-analysis.

The role of dietary calcium in cardiovascular disease prevention is unclear. We aimed to determine the association between calcium intake and incident cardiovascular disease and mortality. Data were extracted from the European Prospective Investigation of Cancer, Norfolk (EPIC-Norfolk). Multivariable Cox regressions analysed associations between calcium intake (dietary and supplemental) and cardiovascular disease (myocardial infarction, stroke, heart failure, aortic stenosis, peripheral vascular disease) and mortality (cardiovascular and all-cause). The results of this study were pooled with those from published prospective cohort studies in a meta-analsyis, stratifying by average calcium intake using a 700 mg/day threshold. A total of 17,968 participants aged 40-79 years were followed up for a median of 20.36 years (20.32-20.38). Compared to the first quintile of calcium intake (< 770 mg/day), intakes between 771 and 926 mg/day (second quintile) and 1074-1254 mg/day (fourth quintile) were associated with reduced all-cause mortality (HR 0.91 (0.83-0.99) and 0.85 (0.77-0.93), respectively) and cardiovascular mortality [HR 0.95 (0.87-1.04) and 0.93 (0.83-1.04)]. Compared to the first quintile of calcium intake, second, third, fourth, but not fifth quintiles were associated with fewer incident strokes: respective HR 0.84 (0.72-0.97), 0.83 (0.71-0.97), 0.78 (0.66-0.92) and 0.95 (0.78-1.15). The meta-analysis results suggest that high levels of calcium intake were associated with decreased all-cause mortality, but not cardiovascular mortality, regardless of average calcium intake. Calcium supplementation was associated with cardiovascular and all-cause mortality amongst women, but not men. Moderate dietary calcium intake may protect against cardiovascular and all-cause mortality and incident stroke. Calcium supplementation may reduce mortality in women.

Anticholinergic burden (prognostic factor) for prediction of dementia or cognitive decline in older adults with no known cognitive syndrome.

BACKGROUND: Medications with anticholinergic properties are commonly prescribed to older adults. The cumulative anticholinergic effect of all the medications a person takes is referred to as the 'anticholinergic burden' because of its potential to cause adverse effects. It is possible that high anticholinergic burden may be a risk factor for development of cognitive decline or dementia. There are various scales available to measure anticholinergic burden but agreement between them is often poor. OBJECTIVES: To assess whether anticholinergic burden, as defined at the level of each individual scale, is a prognostic factor for future cognitive decline or dementia in cognitively unimpaired older adults. SEARCH METHODS: We searched the following databases from inception to 24 March 2021: MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), and ISI Web of Science Core Collection (ISI Web of Science). SELECTION CRITERIA: We included prospective and retrospective longitudinal cohort and case-control observational studies with a minimum of one year' follow-up that examined the association between an anticholinergic burden measurement scale and future cognitive decline or dementia in cognitively unimpaired older adults. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, and undertook data extraction, assessment of risk of bias, and GRADE assessment. We extracted odds ratios (OR) and hazard ratios, with 95% confidence intervals (CI), and linear data on the association between anticholinergic burden and cognitive decline or dementia. We intended to pool each metric separately; however, only OR-based data were suitable for pooling via a random-effects meta-analysis. We initially established adjusted and unadjusted pooled rates for each available anticholinergic scale; then, as an exploratory analysis, established pooled rates on the prespecified association across scales. We examined variability based on severity of anticholinergic burden. MAIN RESULTS: We identified 25 studies that met our inclusion criteria (968,428 older adults). Twenty studies were conducted in the community care setting, two in primary care clinics, and three in secondary care settings. Eight studies (320,906 participants) provided suitable data for meta-analysis. The Anticholinergic Cognitive Burden scale (ACB scale) was the only scale with sufficient data for 'scale-based' meta-analysis. Unadjusted ORs suggested an increased risk for cognitive decline or dementia in older adults with an anticholinergic burden (OR 1.47, 95% CI 1.09 to 1.96) and adjusted ORs similarly suggested an increased risk for anticholinergic burden, defined according to the ACB scale (OR 2.63, 95% CI 1.09 to 6.29). Exploratory analysis combining adjusted ORs across available scales supported these results (OR 2.16, 95% CI 1.38 to 3.38), and there was evidence of variability in risk based on severity of anticholinergic burden (ACB scale 1: OR 2.18, 95% CI 1.11 to 4.29; ACB scale 2: OR 2.71, 95% CI 2.01 to 3.56; ACB scale 3: OR 3.27, 95% CI 1.41 to 7.61); however, overall GRADE evaluation of certainty of the evidence was low. AUTHORS' CONCLUSIONS: There is low-certainty evidence that older adults without cognitive impairment who take medications with anticholinergic effects may be at increased risk of cognitive decline or dementia.

ANTECEDENTES: A los adultos mayores se les prescriben con frecuencia fármacos con propiedades anticolinérgicas. El efecto anticolinérgico acumulado de todos los fármacos que toma una persona se denomina "carga anticolinérgica" por su potencial para causar efectos adversos. Es posible que una alta carga anticolinérgica sea un factor de riesgo para la aparición de un deterioro cognitivo o la demencia. Existen varias escalas para medir la carga anticolinérgica, pero la concordancia entre ellas suele ser mala. OBJETIVOS: Evaluar si la carga anticolinérgica, definida a nivel de cada escala individual, es un factor pronóstico de un futuro deterioro cognitivo o demencia en adultos mayores sin deterioro cognitivo. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las siguientes bases de datos desde su creación hasta el 24 de marzo de 2021: MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost) e ISI Web of Science Core Collection (ISI Web of Science). CRITERIOS DE SELECCIÓN: Se incluyeron los estudios observacionales de cohortes y de casos y controles longitudinales prospectivos y retrospectivos con un seguimiento mínimo de un año, que examinaron la asociación entre una escala de medición de la carga anticolinérgica y el futuro deterioro cognitivo o demencia en adultos mayores sin deterioro cognitivo. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron los estudios para su inclusión y realizaron la extracción de los datos, la evaluación del riesgo de sesgo y la evaluación GRADE. Se extrajeron los odds ratios (OR) y los cociente de riesgos instantáneos, con intervalos de confianza (IC) del 95%, y los datos lineales sobre la asociación entre la carga anticolinérgica y el deterioro cognitivo o la demencia. La intención fue agrupar cada métrica por separado; sin embargo, sólo los datos basados en el OR fueron aptos para agruparlos mediante un metanálisis de efectos aleatorios. Inicialmente se establecieron las tasas agrupadas ajustadas y no ajustadas para cada escala anticolinérgica disponible; luego, como un análisis exploratorio, se establecieron las tasas agrupadas sobre la asociación predeterminada entre las escalas. Se examinó la variabilidad según la intensidad de la carga anticolinérgica. RESULTADOS PRINCIPALES: Se identificaron 25 estudios que cumplían los criterios de inclusión (968 428 adultos mayores). Veinte estudios se realizaron en ámbitos de atención comunitaria, dos en centros de atención primaria y tres en ámbitos de atención secundaria. Ocho estudios (320 906 participantes) proporcionaron datos adecuados para el metanálisis. La escala Anticholinergic Cognitive Burden (escala ACB) fue la única escala con datos suficientes para un metanálisis "basado en la escala". Los OR no ajustados indicaron un aumento en el riesgo de deterioro cognitivo o demencia en los adultos mayores con sobrecarga anticolinérgica (OR 1,47; IC del 95%: 1,09 a 1,96) y los OR ajustados indicaron igualmente un aumento en el riesgo de sobrecarga anticolinérgica, definida según la escala ACB (OR 2,63; IC del 95%: 1,09 a 6,29). El análisis exploratorio que combina los OR ajustados entre las escalas disponibles apoyó estos resultados (OR 2,16; IC del 95%: 1,38 a 3,38) y hubo evidencia de variabilidad en el riesgo según la intensidad de la carga anticolinérgica (1 en escala ACB): OR 2,18; IC del 95%: 1,11 a 4,29; 2 en escala ACB: OR 2,71; IC del 95%: 2,01 a 3,56; 3 en escala ACB: OR 3,27; IC del 95%: 1,41 a 7,61); sin embargo, la evaluación global de la certeza de la evidencia con el método GRADE fue baja. CONCLUSIONES DE LOS AUTORES: Existe evidencia de certeza baja de que los adultos mayores sin deterioro cognitivo que toman fármacos con efectos anticolinérgicos podrían tener un mayor riesgo de deterioro cognitivo o demencia.

Smoking cessation after acute coronary syndrome: A systematic review and meta-analysis.

BACKGROUND: Smoking cessation is an effective secondary prevention measure after acute coronary syndrome (ACS). We conducted a systematic review with the aim to better understand which patients have a greater propensity to quit smoking and the risk factors for continued smoking after ACS. METHODS: We searched MEDLINE and EMBASE for studies that evaluated smoking cessation after ACS. The pooled rate of smoking cessation across included studies was performed. Random effects meta-analysis for different variables and their association with smoking cessation was conducted. RESULTS: A total of 39 studies with 11 228 patients were included in this review. The pooled rate of smoking cessation following ACS across 38 studies was 45.0%. Factors associated with greater likelihood of smoking cessation were attendance at cardiac rehabilitation (OR 1.90 95% CI 1.44-2.51), married/not alone (OR 1.68 95% CI 1.32-2.13), intention/attempt to quit smoking (OR 1.27 95% CI 1.11-1.46), diabetes mellitus (OR 1.24 95% CI 1.03-1.51) and hospitalised duration (OR 1.09 95% CI 1.02-1.15). Variables associated with a lower likelihood of smoking cessation were depression (OR 0.57 95% CI 0.43-0.75), chronic obstructive pulmonary disease/lung disease (OR 0.73 95% CI 0.57-0.93), previous admission with acute myocardial infarction/cardiac admission (OR 0.61 95% CI 0.47-0.80), cerebrovascular disease/transient ischaemic attack (OR 0.42 95% CI 0.30-0.58) and unemployment (OR 0.37 95% CI 0.17-0.80). CONCLUSIONS: The majority of smokers with an ACS continue to smoke after admission. Patients attending cardiac rehabilitation show increased odds of quitting while people who are depressed and those with chronic lung disease were less likely to quit smoking and should be targeted for intensive smoking cessation interventions.

Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study.

BACKGROUND: Sleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia. METHODS: We used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1833 non-sedative-users with sleep disturbance; (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use; and (3) 5172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥ 7.5 mg zopiclone or > 5 mg diazepam daily. Cox regression was used to estimate hazard ratios (HRs) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over a 2-year follow-up, adjusted for demographic- and health-related covariates. RESULTS: The mean (SD) age of patients was 83 (7.7) years, and 16,802 (62%) were women. Of 3532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls, and ischaemic stroke were 1.67 (1.13-2.46), 1.96 (1.16-3.31), 1.33 (1.06-1.66), and 1.88 (1.14-3.10), respectively. We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤ 3.75 mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64-0.83]). CONCLUSIONS: Higher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed. TRIAL REGISTRATION: ENCePP e-register of studies, EUPAS18006.

Propensity score methods in real-world epidemiology: A practical guide for first-time users.

Real-world epidemiology gives us the unique opportunity to observe large numbers of people, and the actions and events that characterize their encounters with healthcare providers. However, the heterogeneity and sheer diversity of the population and healthcare systems makes it impossible for researchers to compare "like with like" when attempting to draw causal inferences about interventions and outcomes. The critical issue in epidemiological datasets relates to high risk of bias due to confounders that stem from baseline differences between groups. Propensity score (PS) techniques are statistical approaches that have been used to tackle potential imbalance in the comparison groups. The PS is the estimated probability (based on measured baseline covariates) that the patient receives a particular intervention. Patients that share similar PS will most likely have the same distributions of underlying covariates included in the PS. Implementation of PS methods may achieve better balance of covariates, but there is no consensus on the best way of capturing all relevant confounders for incorporation into the PS model. Should covariates be selected by clinical or epidemiological experts, or would data-driven algorithms (machine learning) offer more efficient and reliable methods of estimating PS and controlling for confounding? The PS can be incorporated into the analysis in different ways, each with its own strengths and limitations, and researchers must choose the best fit for their study objectives. PS methods are particularly advantageous in situations where there are large numbers of measured covariates but relatively few outcome events captured in healthcare administrative databases.

Efficacy and safety profile of statins in patients with cancer: a systematic review of randomised controlled trials.

PURPOSE: A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies. METHODS: Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364). RESULTS: Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30-1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias. CONCLUSION: The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research.

Anticholinergic drugs and incident dementia, mild cognitive impairment and cognitive decline: a meta-analysis.

BACKGROUND: the long-term effect of the use of drugs with anticholinergic activity on cognitive function remains unclear. METHODS: we conducted a systematic review and meta-analysis of the relationship between anticholinergic drugs and risk of dementia, mild cognitive impairment (MCI) and cognitive decline in the older population. We identified studies published between January 2002 and April 2018 with ≥12 weeks follow-up between strongly anticholinergic drug exposure and the study outcome measurement. We pooled adjusted odds ratios (OR) for studies reporting any, and at least short-term (90+ days) or long-term (365+ days) anticholinergic use for dementia and MCI outcomes, and standardised mean differences (SMD) in global cognition test scores for cognitive decline outcomes. Statistical heterogeneity was measured using the I2 statistic and risk of bias using ROBINS-I. RESULTS: twenty-six studies (including 621,548 participants) met our inclusion criteria. 'Any' anticholinergic use was associated with incident dementia (OR 1.20, 95% confidence interval [CI] 1.09-1.32, I2 = 86%). Short-term and long-term use were also associated with incident dementia (OR 1.23, 95% CI 1.17-1.29, I2 = 2%; and OR 1.50, 95% CI 1.22-1.85, I2 = 90%). 'Any' anticholinergic use was associated with cognitive decline (SMD 0.15; 95% CI 0.09-0.21, I2 = 3%) but showed no statistically significant difference for MCI (OR 1.24, 95% CI 0.97-1.59, I2 = 0%). CONCLUSIONS: anticholinergic drug use is associated with increased dementia incidence and cognitive decline in observational studies. However, a causal link cannot yet be inferred, as studies were observational with considerable risk of bias. Stronger evidence from high-quality studies is needed to guide the management of long-term use.

Association between different methods of assessing blood pressure variability and incident cardiovascular disease, cardiovascular mortality and all-cause mortality: a systematic review.

BACKGROUND: Blood pressure variability (BPV) is a possible risk factor for adverse cardiovascular outcomes and mortality. There is uncertainty as to whether BPV is related to differences in populations studied, measurement methods or both. We systematically reviewed the evidence for different methods to assess blood pressure variability (BPV) and their association with future cardiovascular events, cardiovascular mortality and all-cause mortality. METHODS: Literature databases were searched to June 2019. Observational studies were eligible if they measured short-term BPV, defined as variability in blood pressure measurements acquired either over a 24-hour period or several days. Data were extracted on method of BPV and reported association (or not) on future cardiovascular events, cardiovascular mortality and all-cause mortality. Methodological quality was assessed using the CASP observational study tool and data narratively synthesised. RESULTS: Sixty-one studies including 3,333,801 individuals were eligible. BPV has been assessed by various methods including ambulatory and home-based BP monitors assessing 24-hour, "day-by-day" and "week-to-week" variability. There was moderate quality evidence of an association between BPV and cardiovascular events (43 studies analysed) or all-cause mortality (26 studies analysed) irrespective of the measurement method in the short- to longer-term. There was moderate quality evidence reporting inconsistent findings on the potential association between cardiovascular mortality, irrespective of methods of BPV assessment (17 studies analysed). CONCLUSION: An association between BPV, cardiovascular mortality and cardiovascular events and/or all-cause mortality were reported by the majority of studies irrespective of method of measurement. Direct comparisons between studies and reporting of pooled effect sizes were not possible.

Can cardiovascular risk management be improved by shared care with general practice to prevent cognitive decline following stroke/TIA? A feasibility randomised controlled trial (SERVED memory).

BACKGROUND: Cognitive impairment and dementia following cerebrovascular disease are increasingly common in the UK. One potential strategy to prevent post-stroke cognitive decline is multimodal vascular risk factor management. However, its efficacy remains uncertain and its application in vulnerable patients with incident cerebrovascular disease and early cognitive impairment has not been assessed. The primary aim of this study was to assess the feasibility of recruitment and retention of patients with early cognitive impairment post-stroke or transient ischaemic attack (TIA) to a trial of enhanced vascular risk factor management combining primary and secondary care. METHODS: In this single centre, open label trial adults with a recent stroke or TIA and mild cognitive impairment (MCI) were randomised 1:1 to a three-monthly multimodal vascular risk factor intervention jointly delivered by the trial team and General Practitioner (GP), or control (defined as usual care from the GP). Chosen risk factors were blood pressure (BP), total cholesterol, blood glucose (HbA1C) in those with diabetes, and heart rate and adequacy of anticoagulation in those with atrial fibrillation (AF). Similar patients with normal cognition were enrolled in an embedded observational cohort and also received usual care from the GP. Repeat cognitive screening was undertaken in all participants after 12 months. RESULTS: Seventy three participants were recruited to the randomised trial and 94 to the observational cohort (21.8% of those screened). From the randomised trial 35/73 (47.9%) dropped out before final follow-up. In all groups guideline based rates of risk factor control were mostly poor at baseline and did not significantly improve during follow-up. The observational cohort demonstrated greater decline in cognitive test scores at 12 months, with no difference between the randomised groups. CONCLUSIONS: Recruitment to such a study was feasible, but retention of participants was difficult and generally poor rates of risk factor control suggested insufficient application of the intervention. Consequently, successful scaling up of the trial would require protocol changes with less reliance on primary care services. Any future trial should include participants with normal cognition post-stroke as they may be at greatest risk of cognitive decline. TRIAL REGISTRATION: ISRCTN, ISRCTN42688361 . Registered 16 April 2015.

Increasing prevalence of anticholinergic medication use in older people in England over 20 years: cognitive function and ageing study I and II.

BACKGROUND: Anticholinergic medication use is linked with increased cognitive decline, dementia, falls and mortality, and their use should be limited in older people. Here we estimate the prevalence of anticholinergic use in England's older population in 1991 and 2011, and describe changes in use by participant's age, sex, cognition and disability. METHODS: We compared data from participants aged 65+ years from the Cognitive Function and Ageing Studies (CFAS I and II), collected during 1990-1993 (N = 7635) and 2008-2011 (N = 7762). We estimated the prevalence of potent anticholinergic use (Anticholinergic Cognitive Burden [ACB] score = 3) and average anticholinergic burden (sum of ACB scores), using inverse probability weights standardised to the 2011 UK population. These were stratified by age, sex, Mini-Mental State Examination score, and activities of daily living (ADL) or instrumental ADL (IADL) disability. RESULTS: Prevalence of potent anticholinergic use increased from 5.7% (95% Confidence Interval [CI] 5.2-6.3%) of the older population in 1990-93 to 9.9% (9.3-10.7%) in 2008-11, adjusted odds ratio of 1.90 (95% CI 1.67-2.16). People with clinically significant cognitive impairment (MMSE [Mini Mental State Examination] 21 or less) were the heaviest users of potent anticholinergics in CFAS II (16.5% [95% CI 12.0-22.3%]). Large increases in the prevalence of the use medication with 'any' anticholinergic activity were seen in older people with clinically significant cognitive impairment (53.3% in CFAS I to 71.5% in CFAS II). CONCLUSIONS: Use of potent anticholinergic medications nearly doubled in England's older population over 20 years with some of the greatest increases amongst those particularly vulnerable to anticholinergic side-effects.

History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study.

Previous estimates of whether long-term exposure to benzodiazepines increases dementia risk are conflicting and are compromised by the difficulty of controlling for confounders and by reverse causation. We investigated how estimates for the association between benzodiazepine use and later dementia incidence varied based on study design choices, using a case-control study nested within the United Kingdom's Clinical Practice Research Datalink. A total of 40,770 dementia cases diagnosed between April 2006 and July 2015 were matched on age, sex, available data history, and deprivation to 283,933 control subjects. Benzodiazepines and Z-drug prescriptions were ascertained in a drug-exposure period 4-20 years before dementia diagnosis. Estimates varied with the inclusion of new or prevalent users, with the timing of covariate ascertainment, and with varying time between exposure and outcome. There was no association between any new prescription of benzodiazepines and dementia (adjusted odds ratio (OR) = 1.03, 95% confidence interval (CI): 1.00, 1.07), whereas an inverse association was observed among prevalent users (adjusted OR = 0.91, 95% CI: 0.87, 0.95), although this was likely induced by unintentional adjustment for colliders. By considering the choice of confounders and timing of exposure and covariate measurement, our findings overall are consistent with no causal effect of benzodiazepines or Z-drugs on dementia incidence.

The effects of hypoglycaemia and dementia on cardiovascular events, falls and fractures and all-cause mortality in older individuals: A retrospective cohort study.

AIMS: Older individuals with diabetes are susceptible to harm as the result of hypoglycaemia; however, the consequences of hypoglycaemia in older individuals with dementia are not known. We aimed to test the association between hypoglycaemia and serious adverse events in older patients with diabetes and dementia, and whether the consequences of hypoglycaemia were affected by the presence of dementia. MATERIALS AND METHODS: This was a cohort study using the Clinical Practice Research Datalink in England (1997-2016). We selected participants, intervention (exposure) and follow-up to mirror two hypothetical target randomized controlled trials. The exposure of target trial 1 was hypoglycaemia in patients with dementia. Target trial 2 examined adverse effects of hypoglycaemia according to dementia status. We used Cox proportional hazard regression to estimate adjusted hazard ratios (aHR) for falls, fractures, cardiovascular events and mortality. RESULTS: In target trial 1, hypoglycaemia was associated with increased risk during a 12-month follow-up period for falls and fractures (aHR, 1.94 [95% CI, 1.67-2.24]), for cardiovascular events (aHR, 2.00 [95% CI, 1.61-2.48]) and for mortality (aHR, 2.36 [95% CI, 2.09-2.67]). In target trial 2, the presence of dementia was associated with increased risk of adverse events, following hypoglycaemia, during a 12-month follow-up period for falls and factures (aHR, 1.72 [95% CI, 1.51-1.96]) and for mortality (aHR, 1.27 [95% CI, 1.15-1.41]), but dementia had no effect on cardiovascular events (aHR, 1.14 [95% CI, 0.95 to 1.36]). CONCLUSIONS: Hypoglycaemia is associated with early increased risk of serious adverse events in older individuals with diabetes and dementia.