New Adverse Drug Reaction Signals from 2017 to 2021-Genuine Alerts or False Alarms?

Spontaneous adverse events reporting systems are used internationally to flag new or unexpected adverse drug reactions (ADRs). Disproportionality analysis is a recognised technique, but false alarms may arise. We aimed to determine whether these new ADR signals had subsequently been followed-up with detailed hypothesis-testing studies. We searched PubMed to identify published studies (years 2017-2021) where the authors reported findings of new ADR signals from disproportionality analyses. We used PubMed and forward citation tracking (Google Scholar) to identify any subsequent confirmatory studies of these ADR signals. We screened 414 titles and abstracts and checked the full-text articles of 57 studies. We found signals for 56 suspected new ADRs from 24 drugs. Google Scholar showed that the ADR studies had been cited a median of seven times (range 0-61). However, none of the suspected new ADRs had undergone detailed evaluation in the citing literature. Similarly, our PubMed search did not find any confirmation studies for the 56 suspected new ADRs. Although many suspected new ADR signals have been identified through disproportionality analysis, most signals have not been further verified as being either genuine ADRs or false alarms. Researchers must focus on follow-up studies for these new signals.

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.

Meta-Analysis: Association Between Hypoglycemia and Serious Adverse Events in Older Patients Treated With Glucose-Lowering Agents.

Aims: We conducted a meta-analysis of serious adverse events (dementia, macro- and micro-vascular events, falls and fractures, and death) associated with hypoglycemia in older patients treated with glucose lowering drugs. Materials and Methods: Meta-analysis of studies reporting on hypoglycemia and adverse events. The search included studies from two previously published systematic reviews, and an updated search of MEDLINE and EMBASE from April 2014 to November 2019. We assessed study validity based on ascertainment of hypoglycemia, adverse events and adjustment for confounders, and conducted a random effects meta-analyses, assessing heterogeneity using the I2 statistic. Results: We included 44 studies involving 2,507,434 participants. Most of the studies used adjusted analysis for confounders and hypoglycaemic events were typically identified based on healthcare databases (severe events). Hypoglycemia was associated with increased likelihood of death in a meta-analysis of eighteen studies, pooled OR 2.02 (95% Confidence Interval 1.75-2.32). Studies assessing mortality signal a time-response relationship with a higher risk of adverse events occurring within the first 90 days after hypoglycemia. Our meta-analysis of nine studies demonstrated that hypoglycaemic episodes were associated with dementia - pooled OR 1.50 (95% CI 1.29-1.74). Our meta-analysis of nineteen studies demonstrated associations between hypoglycaemia and macrovascular complications, pooled OR 1.81 (95% CI 1.70-1.94), and microvascular complications (two studies) pooled OR 1.77 (95% CI 1.49-2.10). There is also an association between hypoglycemia and cardiovascular death (six studies) - pooled OR 2.11 (95% CI 1.55 to 2.87). Similarly, our meta-analysis of six studies demonstrated an association between hypoglycemia and falls and fractures, pooled OR 1.78 (95% CI 1.44-2.21) and 1.68 (95% CI 1.37-2.07) respectively. Conclusion: This meta-analysis confirms previously reported concerns of serious harm following hypoglycemia, especially in the immediate time period after a hypoglycaemic event. Avoidance of hypoglycaemic episodes should be a priority in this vulnerable population.

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.

Continuous glucose monitoring in older people with diabetes and memory problems: a mixed-methods feasibility study in the UK.

OBJECTIVES: Older people with diabetes are at increased risk of harm from hypoglycaemia, particularly where there are coexisting memory problems. Continuous glucose monitoring (CGM) offers important benefits in terms of detecting hypoglycaemia, but the feasibility of use and extent of data capture has not been tested in this patient group. Our objective was to investigate the feasibility of trialling a CGM intervention in the community setting in older people with diabetes and memory problems. DESIGN: Mixed-methods feasibility study. SETTING: Community dwellings in the UK. PARTICIPANTS: Patients aged ≥65 with diabetes and abbreviated mental test score ≤8 or known dementia. INTERVENTION: FreeStyle Libre CGM. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility criteria were numbers of eligible patients, recruitment, attrition, extent of capture of glucose readings and adverse events. Qualitative interview. RESULTS: We identified 49 eligible participants; 17 consented, but 5 withdrew before recording of data because they or their carers felt unable to manage study procedures. 12 participants (mean age 85 years) completed the study without adverse events. Data capture across 14 days ranged between 3% and 92% (mean 55%); 6 participants had <60% capture. Hypoglycaemic events were recorded in six out of nine insulin users. Qualitative interviews found: the device does not interfere with daily activities, usability and comfort was positive, and it was helpful for carers in monitoring participants' glucose concentrations. CONCLUSIONS: The device was acceptable to participants, and carers reported greater ease in monitoring the participant's glucose concentrations. However, completeness of data capture varied considerably with this device due to the need for users to conduct ≥3 scans per day. Real-time devices with automated data transfer may be more suitable in older people with memory problems.

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.

Safety of 80% vs 30-35% fraction of inspired oxygen in patients undergoing surgery: a systematic review and meta-analysis.

BACKGROUND: Evidence-based guidelines from the World Health Organization (WHO) have recommended a high (80%) fraction of inspired oxygen (FiO2) to reduce surgical site infection in adult surgical patients undergoing general anaesthesia with tracheal intubation. However, there is ongoing debate over the safety of high FiO2. We performed a systematic review to define the relative risk of clinically relevant adverse events (AE) associated with high FiO2. METHODS: We reviewed potentially relevant articles from the WHO review supporting the recommendation, including an updated (July 2018) search of EMBASE and PubMed for randomised and non-randomised controlled studies reporting AE in surgical patients receiving 80% FiO2 compared with 30-35% FiO2. We assessed study quality and performed meta-analyses of risk ratios (RR) comparing 80% FiO2 against 30-35% for major complications, mortality, and intensive care admission. RESULTS: We included 17 moderate-good quality trials and two non-randomised studies with serious-critical risk of bias. No evidence of harm with high FiO2 was found for major AE in the meta-analysis of randomised trials: atelectasis RR 0.91 [95% confidence interval (CI) 0.59-1.42); cardiovascular events RR 0.90 (95% CI 0.32-2.54); intensive care admission RR 0.93 (95% CI 0.7-1.12); and death during the trial RR 0.49 (95% CI 0.17-1.37). One non-randomised study reported that high FiO2 was associated with major respiratory AE [RR 1.99 (95% CI 1.72-2.31)]. CONCLUSIONS: No definite signal of harm with 80% FiO2 in adult surgical patients undergoing general anaesthesia was demonstrated and there is little evidence on safety-related issues to discourage its use in this population.

Anticholinergic drugs and risk of dementia: case-control study.

OBJECTIVES: To estimate the association between the duration and level of exposure to different classes of anticholinergic drugs and subsequent incident dementia. DESIGN: Case-control study. SETTING: General practices in the UK contributing to the Clinical Practice Research Datalink. PARTICIPANTS: 40 770 patients aged 65-99 with a diagnosis of dementia between April 2006 and July 2015, and 283 933 controls without dementia. INTERVENTIONS: Daily defined doses of anticholinergic drugs coded using the Anticholinergic Cognitive Burden (ACB) scale, in total and grouped by subclass, prescribed 4-20 years before a diagnosis of dementia. MAIN OUTCOME MEASURES: Odds ratios for incident dementia, adjusted for a range of demographic and health related covariates. RESULTS: 14 453 (35%) cases and 86 403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. The adjusted odds ratio for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14). Dementia was associated with an increasing average ACB score. When considered by drug class, gastrointestinal drugs with an ACB score of 3 were not distinctively linked to dementia. The risk of dementia increased with greater exposure for antidepressant, urological, and antiparkinson drugs with an ACB score of 3. This result was also observed for exposure 15-20 years before a diagnosis. CONCLUSIONS: A robust association between some classes of anticholinergic drugs and future dementia incidence was observed. This could be caused by a class specific effect, or by drugs being used for very early symptoms of dementia. Future research should examine anticholinergic drug classes as opposed to anticholinergic effects intrinsically or summing scales for anticholinergic exposure. TRIAL REGISTRATION: Registered to the European Union electronic Register of Post-Authorisation Studies EUPAS8705.

Protocol for a feasibility randomised controlled trial of Screening and Enhanced Risk management for Vascular Event-related Decline in Memory (SERVED Memory).

INTRODUCTION: Stroke is a leading cause of death and disability. The development of dementia after stroke is common. Vascular risk factors (VRF) which contribute to stroke risk can also contribute to cognitive decline, especially in vascular dementia (VaD). There is no established treatment for VaD, therefore strategies for prevention could have major health resource implications. This study was designed to assess whether patients with early cognitive decline after stroke/transient ischaemic attack (TIA) can be easily identified and whether target-driven VRF management can prevent progression to dementia. OBJECTIVES: The primary objective is to establish the feasibility of recruitment and retention of patients with early cognitive decline to a randomised controlled trial of enhanced VRF management. Secondary objectives include: (a) to determine the potential clinical benefit of the intervention; (b) to estimate the sample size for a future definitive multicentre randomised controlled trial; (c) to inform a future economic evaluation; (d) to explore the link between VRF control and the incidence of cognitive impairment on longitudinal follow-up in a UK population after stroke/TIA with current routine management. METHODS: 100 patients with cognitive decline poststroke/TIA will be recruited from stroke services at the Norfolk and Norwich University Hospital. After collection of baseline data, they will be randomised to intervention (3 monthly follow-up with enhanced management) or control (treatment as usual by the general practitioner). At 12 months outcomes (repeat cognitive testing, VRF assessment) will be assessed. A further 100 patients without cognitive decline will be recruited to a parallel observational group from the same site. At 12 months they will have repeat cognitive testing. ETHICS AND DISSEMINATION: Ethical approval has been granted in England. Dissemination is planned via publication in peer-reviewed medical journals and presentation at relevant conferences. TRIAL REGISTRATION NUMBER: 42688361; Pre-results.

Meta-analysis: Association between hypoglycaemia and serious adverse events in older patients.

AIMS: We aimed to conduct a meta-analysis of serious adverse events (macro- and microvascular events, falls and fractures, death) associated with hypoglycaemia in older patients. METHODS: We searched MEDLINE and EMBASE spanning a ten-year period up to March 2015 (with automated PubMed updates to October 2015). We selected observational studies reporting on hypoglycaemia and associated serious adverse events, and conducted a meta-analysis. We assessed study validity based on ascertainment of hypoglycaemia, adverse events and adjustment for confounders. RESULTS: We included 17 studies involving 1.86 million participants. Meta-analysis of eight studies demonstrated that hypoglycemic episodes were associated with macrovascular complications, odds ratio (OR) 1.83 (95% confidence interval [CI] 1.64, 2.05), and microvascular complications in two studies OR 1.77 (95% CI 1.49, 2.10). Meta-analysis of four studies demonstrated an association between hypoglycaemia and falls or fractures, OR 1.89 (95% CI 1.54, 2.32) and 1.92 (95% CI 1.56, 2.38) respectively. Hypoglycaemia was associated with increased likelihood of death in a meta-analysis of eight studies, OR 2.04 (95% Confidence Interval 1.68, 2.47). CONCLUSION: Our meta-analysis raises major concerns about a range of serious adverse events associated with hypoglycaemia. Clinicians should prioritize individualized therapy and closer monitoring strategies to avoid hypoglycaemia in susceptible older patients.

Prognostic Tools for Early Mortality in Hemorrhagic Stroke: Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Several risk scores have been developed to predict mortality in intracerebral hemorrhage (ICH). We aimed to systematically determine the performance of published prognostic tools. METHODS: We searched MEDLINE and EMBASE for prognostic models (published between 2004 and April 2014) used in predicting early mortality (<6 months) after ICH. We evaluated the discrimination performance of the tools through a random-effects meta-analysis of the area under the receiver operating characteristic curve (AUC) or c-statistic. We evaluated the following components of the study validity: study design, collection of prognostic variables, treatment pathways, and missing data. RESULTS: We identified 11 articles (involving 41,555 patients) reporting on the accuracy of 12 different tools for predicting mortality in ICH. Most studies were either retrospective or post-hoc analyses of prospectively collected data; all but one produced validation data. The Hemphill-ICH score had the largest number of validation cohorts (9 studies involving 3,819 patients) within our systematic review and showed good performance in 4 countries, with a pooled AUC of 0.80 [95% confidence interval (CI)=0.77-0.85]. We identified several modified versions of the Hemphill-ICH score, with the ICH-Grading Scale (GS) score appearing to be the most promising variant, with a pooled AUC across four studies of 0.87 (95% CI=0.84-0.90). Subgroup testing found statistically significant differences between the AUCs obtained in studies involving Hemphill-ICH and ICH-GS scores (p=0.01). CONCLUSIONS: Our meta-analysis evaluated the performance of 12 ICH prognostic tools and found greater supporting evidence for 2 models (Hemphill-ICH and ICH-GS), with generally good performance overall.

Meta-review: adverse effects of inhaled corticosteroids relevant to older patients.

BACKGROUND: In recent years, clinical trials and observational studies have raised concerns about the potential adverse effects of inhaled corticosteroids (ICS) such as pneumonia, cataract, fractures and hyperglycaemia, which are of particular concern for older patients. METHODS: We conducted a meta-review by searching electronic databases (MEDLINE, EMBASE, PubMed) for systematic reviews and meta-analyses of ICS use and the adverse effects of interest. We also evaluated new primary studies that reported information beyond that available from previously published meta-analyses. Two reviewers independently extracted data on measures of associated harm with ICS use. RESULTS: We identified five relevant meta-analyses for inclusion in this meta-review, and also three new studies of ICS and pneumonia. We found consistent evidence of a dose-response relationship between ICS use and serious adverse effects such as fractures and pneumonia. The estimated number needed to treat for harm due to fracture with ICS was 83 with 3-years use, and 60 per year for pneumonia. Both asthma and chronic obstructive pulmonary disease (COPD) users of ICS were at risk of pneumonia, with fluticasone appearing to confer higher risk than budesonide. There is also some suggestion that ICS use is associated with cataracts in a dose-response manner but the evidence is less robust here. Equally, the influence of ICS on diabetes mellitus remains uncertain. CONCLUSIONS: In view of the dose-response relationship seen between ICS use and important adverse effects such as fractures and pneumonia, clinicians needs to carefully balance the benefits of ICS versus the harms in older patients receiving long-term high-dose ICS.