Cardiorenal effects of Angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers in people underrepresented in trials: analysis of routinely collected data with emulation of a reference trial (ONTARGET).

Cardiovascular disease (CVD) is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial, each prevent CVD. However, trial results may not be generalisable and their effectiveness in underrepresented groups is unclear. Using trial emulation methods within routine-care data to validate findings, we explored generalisability of ONTARGET results. For people prescribed an ACEi/ARB in the UK Clinical Practice Research Datalink GOLD from 1/1/2001-31/7/2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB to ACEi, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), and secondary outcomes. As the pre-specified criteria were met confirming trial emulation, we then explored treatment heterogeneity among three trial-underrepresented subgroups: females, those aged ≥75 years and those with chronic kidney disease (CKD). In the trial-eligible population (n=137,155), results for the primary outcome demonstrated similar effects of ARB and ACEi, (HR 0.97 [95% CI: 0.93, 1.01]), meeting the pre-specified validation criteria. When extending this outcome to trial-underrepresented groups, similar treatment effects were observed by sex, age and CKD. This suggests that ONTARGET trial findings are generalisable to trial-underrepresented subgroups.

Potential interactions between medications for rate control and direct oral anticoagulants: population-based cohort and case-crossover study.

BACKGROUND: Direct oral anticoagulants (DOACs) are commonly co-prescribed with amiodarone/diltiazem/verapamil, but whether there is a drug interaction between these drugs is unclear. OBJECTIVE: To investigate the risk of clinical outcomes associated with concomitant use of DOACs and amiodarone/diltiazem/verapamil. METHODS: We identified DOAC users in the Clinical Practice Research Datalink Aurum from 1/1/2011-31/12/2019. We used a cohort design to estimate hazard ratios for Ischaemic stroke, myocardial infarction, venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, other bleeding, cardiovascular mortality, and all-cause mortality comparing DOACs+amiodarone/diltiazem/verapamil users, respectively and DOACs+beta-blocker users. A case-crossover design comparing odds of exposure to different drug initiation patterns for all outcomes in hazard window versus referent window within an individual was also conducted. RESULTS: Of 397,459 DOAC users, we included 9075 co-prescribed amiodarone, 9612 co-prescribed diltiazem, and 2907 co-prescribed verapamil. There was no difference in risk of any outcomes between DOACs+amiodarone/diltiazem/verapamil users, respectively versus DOACs+beta-blocker users in cohort design. However, in case-crossover design, we observed an odds ratio (OR) of 2.09 (99%CI: 1.37-3.18) for all-cause mortality associated with an initiation of a DOAC while taking amiodarone; which was greater than that observed for DOAC monotherapy (OR: 1.30; 99%CI: 1.25-1.35). Similar findings were observed for cardiovascular mortality and all-cause mortality respectively with diltiazem. CONCLUSIONS: Our study shows no evidence of higher bleeding or cardiovascular risk associated with co-prescribed DOACs and amiodarone, diltiazem or verapamil respectively. The elevated risks of cardiovascular and all-cause mortality were only observed during DOAC initiation when diltiazem/amiodarone were being taken.

Systemic Fluoroquinolone Use and Risk of Uveitis or Retinal Detachment.

Importance: Fluoroquinolone use has been associated with increased risk of uveitis and retinal detachment in noninterventional studies, but the findings have been conflicting and causality is unclear. Objective: To estimate the association of systemic fluoroquinolone use with acute uveitis or retinal detachment, using multiple analyses and multiple databases to increase the robustness of results. Design, Setting, and Participants: This cohort study used data from the Clinical Practice Research Datalink Aurum and GOLD UK primary care records databases, which were linked to hospital admissions data. Adults prescribed a fluoroquinolone or a comparator antibiotic, cephalosporin, between April 1997 and December 2019 were included. Adults with uveitis or retinal detachment were analyzed in a separate self-controlled case series. Data analysis was performed from May 2022 to May 2023. Exposures: Systemic fluoroquinolone or comparator antibiotic. Main Outcomes and Measures: The primary outcome was a diagnosis of acute uveitis or retinal detachment. Hazard ratios (HRs) were estimated in the cohort study for the association of fluoroquinolone prescription with either uveitis or retinal detachment, using stabilized inverse probability of treatment weighted Cox regression. Rate ratios (RRs) were estimated in the self-controlled case series, using conditional Poisson regression. Estimates were pooled across databases using fixed-effects meta-analysis. Results: In total, 3 001 256 individuals in Aurum (1 893 561 women [63.1%]; median [IQR] age, 51 [35-68] years) and 434 754 in GOLD (276 259 women [63.5%]; median [IQR] age, 53 [37-70] years) were included in the cohort study. For uveitis, the pooled adjusted HRs (aHRs) for use of fluoroquinolone vs cephalosporin were 0.91 (95% CI, 0.72-1.14) at first treatment episode and 1.07 (95% CI, 0.92-1.25) over all treatment episodes. For retinal detachment, the pooled aHRs were 1.37 (95% CI, 0.80-2.36) at first treatment episode and 1.18 (95% CI, 0.84-1.65) over all treatment episodes. In the self-controlled case series, for uveitis, the pooled adjusted RRs (aRRs) for fluoroquinolone use vs nonuse were 1.13 (95% CI, 0.97-1.31) for 1 to 29 days of exposure, 1.16 (95% CI, 1.00-1.34) for 30 to 59 days, and 0.98 (95% CI, 0.74-1.31) for 60 days for longer. For retinal detachment, pooled aRRs for fluoroquinolone use vs nonuse were 1.15 (95% CI, 0.86-1.54) for 1 to 29 days of exposure, 0.94 (95% CI, 0.69-1.30) for 30 to 59 days, and 1.03 (95% CI, 0.59-1.78) for 60 days or longer. Conclusions and Relevance: These findings do not support an association of systemic fluoroquinolone use with substantively increased risk of uveitis or retinal detachment. Although an association cannot be completely ruled out, these findings indicate that any absolute increase in risk would be small and, hence, of limited clinical importance.

Feasibility of High-Frequency Monitoring of the Home Environment and Health in Older Adults: Proof of Concept.

Technology provides new opportunities to understand and optimize the relationship between the home indoor environmental quality and health outcomes in older adults. We aimed to establish proof-of-concept and feasibility of remote, real-time, high-frequency, and simultaneous monitoring of select environmental variables and outcomes related to health and wellbeing in older adults. Thirty-four participants (27 were female) with an average age (SD) of 81 years (±7.1) were recruited from community and supportive housing environments. Environmental sensors were installed in each home and participants were asked to use a wearable device on their finger and answer smartphone-based questionnaires on a daily basis. Further, a subgroup of participants were asked to complete tablet-based cognitive tests on a daily basis. Average compliance with the wearable (time worn properly / total time with device) was 81%. Participants responded to 69% of daily smartphone surveys and completed 80% of the prescribed cognitive tests. These results suggest that it is feasible to study the impact of the home thermal environment and air quality on biological rhythms, cognition, and other outcomes in older adults. However, the success of non-passive data collection elements may be contingent upon baseline cognition.

An acoustical environment survey of student music practice.

Chronic exposure to loud sound leads to noise-induced hearing loss. This is especially common in collegiate-level musicians. Existing methods for estimating exposure typically do not consider genre- or instrument-specific variability in soundscape/spectral characteristics. We measured sound exposure levels (SELs) across instruments, bands, and genres at a university music school. We found (1) considerable variability in SELs across instruments and bands, (2) that Jazz musicians are consistently exposed to the highest sound levels, and (3) that spectral features of music differ between instrument type and genre, and based on room size. These findings highlight the need for tailored guidelines that moderate the implementation of hearing conservation initiatives for collegiate musicians.

Effects of sequential vs single pneumococcal vaccination on cardiovascular diseases among older adults: a population-based cohort study.

BACKGROUND: Recommendations around the use of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13) seldom focus on potential benefits of vaccine on comorbidities. We aimed to investigate whether sequential vaccination with PCV13 and PPSV23 among older adults would provide protection against cardiovascular diseases (CVD) compared with using a single pneumococcal vaccine. METHODS: We conducted a Hong Kong-wide retrospective cohort study between 2012 and 2020. Adults aged ≥65 years were identified as receiving either a single or sequential dual vaccination and followed up until the earliest CVD occurrence, death or study end. To minimize confounding, we matched each person receiving a single vaccination to a person receiving sequential vaccination according to their propensity scores. We estimated the hazard ratio (HR) of CVD risk using Cox regression and applied structural equation modelling to test whether the effect of sequential dual vaccination on CVD was mediated via the reduction in pneumonia. RESULTS: After matching, 69 390 people remained in each group and the median (interquartile range) follow-up time was 1.89 (1.55) years. Compared with those receiving a single vaccine, those receiving sequential dual vaccination had a lower risk of CVD [HR (95% CI): 0.75 (0.71, 0.80), P < 0.001]. Post-hoc mediation analysis showed strong evidence that the decreased CVD risk was mediated by the reduction in all-cause pneumonia. CONCLUSIONS: Sequential dual pneumococcal vaccination was associated with lower risk of CVD compared with single-dose PCV13 or PPSV23 in older adults. Such additional CVD benefits should be considered when making decisions about pneumococcal vaccination.

Assessment of Autonomic Nervous System Activity Using Spectral Analysis of Heart Rate Variability After Continuous Positive Airway Pressure (CPAP) Therapy in Patients With Sleep Apnea.

Heart rate variability (HRV) measurements have emerged as a valuable tool for understanding the functioning of the autonomic nervous system (ANS) and assessing the health outcomes of obstructive sleep apnea (OSA) in patients. Sleep and the ANS exert a mutual influence on each other. Sleep promotes relaxation and recovery of the ANS. Conversely, ANS activity plays a role in regulating the onset and maintenance of sleep. The impact of continuous positive airway pressure (CPAP) therapy on patient recovery levels was investigated by assessing the restoration of ANS activity using HRV indicators. The study included patients with OSA who had been on CPAP for at least eight weeks. The patients were divided into two groups, namely the experimental group (CPAP-compliant) and the control group (CPAP-non-compliant). The study included a total of 38 patients, with 20 in the CPAP-compliant group and 18 in the CPAP-non-compliant group. The HRV analysis included time- and frequency-domain measures. Data was collected in various resting conditions, including lying down, standing, regular breathing, and under physiological stress induced by deep breathing and the Valsalva maneuver. After CPAP treatment, there was an increase in the average values for SDNN for deep breathing and Valsalva maneuvers. The mean changes in SDNN for CPAP-non-compliant versus CPAP-compliant groups for normal breathing increased from 32.50±5.33 to 42.40±8.03, while the values for Valsalva increased from 20.16±2.47 to 25.45±3.03. Despite the observed variations in SDNN, there was no significant change in the average change in heart rate (∆ HR), except during the Valsalva maneuver. Post-CPAP values for the Valsalva ratio were significantly decreased in deep breathing. The E:I ratio for the CPAP-compliant group during normal breathing was 1.08±.16 compared to 1.55±.09; t (36) =-11.15, p <0.001 in the CPAP-non-compliant group. During deep breathing, the ratio was 1.36±.15 versus 1.59±.24; t (36) =-3.578, p <0.001. The high frequency (HF)nu mean values for deep breathing were 34.06±5.546 compared to 35.00±6.358; t (36) = -.485, p=.630. For the Valsalva maneuver, the values were 29.94±4.721 versus 26.95±6.621; t (36) =1.589, p=.060. The HF/low frequency (LF) ratio was found to be significant only in supine, standing, and normal breathing. The utilization of CPAP therapy was found to be effective in achieving and sustaining autonomic balance during tasks like standing and engaging in regular breathing patterns. During activities that involve intense physical effort, like the Valsalva maneuver, the HRV metrics did not indicate any significant balance between sympathetic and parasympathetic activity. However, using CPAP therapy for a prolonged period can be beneficial in consistently improving the sympathovagal balance in these patients.

Implementation of a Taxonomy-Based Framework for the Selection of Appropriate Drugs and Outcomes for Real-World Data Signal Detection Studies.

INTRODUCTION: For signal detection studies investigating either drug safety or method evaluation, the choice of drug-outcome pairs needs to be tailored to the planned study design and vice versa. While this is well understood in hypothesis-testing epidemiology, it should be as important in signal detection, but this has not widely been considered. There is a need for a taxonomy framework to provide guidance and a systematic reproducible approach to the selection of appropriate drugs and outcomes for signal detection studies either investigating drug safety or assessing method performance using real-world data. OBJECTIVE: The aim was to design a general framework for the selection of appropriate drugs and outcomes for signal detection studies given a study design of interest. As a motivating example, we illustrate how the framework is applied to build a reference set for a study aiming to assess the performance of the self-controlled case series with active comparators. METHODS: We reviewed criteria presented in two published studies which aimed to provide practical advice for choosing the appropriate signal evaluation methodology, and assessed their relevance for signal detection. Further characteristics specific to signal detection were added. The final framework is based on: the application of study design requirements, the database(s) of interest, and the clinical importance of the drug(s) and outcome(s) under consideration. This structure was applied by selecting drug-outcome pairs as a reference set (i.e. list of drug-outcome pairs classified as positive or negative controls) for which the method is expected to work well for a signal detection study aiming to assess the performance of self-controlled case series. Eight criteria were used, related to the application of self-controlled case series assumptions, choice of active comparators, coverage in the database of interest and clinical importance of the outcomes. RESULTS: After application of the framework, two classes of antibiotics (seven drugs) were selected for the study, and 28 outcomes from all organ classes were chosen from the drug labels, out of the 273 investigated. In total, this corresponds to 104 positive controls (drug-outcome pairs) and 58 negative controls. CONCLUSIONS: We proposed and applied a framework for the selection of drugs and outcomes for both drug safety signal detection and method assessment used in signal detection to optimise their performance given a study design. This framework will eliminate part of the bias relating to drugs and outcomes not being suited to the method or database. The main difficulty lies in the choice of the criteria and their application to ensure systematic selection, especially as some information remains unknown in signal detection, and clinical judgement was needed on occasions. The same framework could be adapted for other methods.

Association Between Fluoroquinolone Use and Hospitalization With Aortic Aneurysm or Aortic Dissection.

Importance: Fluoroquinolone use has been associated with increased hospitalization with aortic aneurysm or dissection in noninterventional studies, but the reason for this observed association is unclear. Objective: To determine the association between fluoroquinolone use and aortic aneurysm or dissection using multiple study designs and multiple databases to increase the robustness of findings. Design, Setting, and Participants: Cohort and case-crossover studies were conducted separately in 2 databases of UK primary care records. Clinical Practice Research Datalink Aurum and GOLD primary care records were linked to hospital admissions data. Adults with a systemic fluoroquinolone or cephalosporin prescription between April 1997 and December 2019 were included in the cohort study. Adults hospitalized with aortic aneurysm or dissection within the eligibility period were included in the case-crossover study. Individuals meeting inclusion criteria in the case-crossover study were matched 1:3 to control individuals on age, sex, index date, and clinical practice to adjust for calendar trends in prescribing. Data were analyzed from January to July 2022. Exposures: Systemic fluoroquinolone or comparator antibiotic. Main Outcomes and Measures: Hazard ratios (HRs) were estimated in the cohort study for the association between prescription of fluoroquinolones and hospitalization with aortic aneurysm or dissection using stabilized inverse probability of treatment-weighted Cox regression. Odds ratios (OR) were estimated in the case-crossover study for the association between systemic fluoroquinolone use and hospitalization with aortic aneurysm or dissection using a conditional logistic regression model. Estimates were pooled across databases using fixed-effects meta-analysis. Results: In the cohort study, we identified 3 134 121 adults in Aurum (mean [SD] age, 52.5 [20.3] years; 1 969 257 [62.8%] female) and 452 086 in GOLD (mean [SD] age, 53.9 [20.2] years; 286 502 [63.4%] female) who were prescribed fluoroquinolones or cephalosporins. In crude analyses, fluoroquinolone relative to cephalosporin use was associated with increased hospitalization with aortic aneurysm or dissection (pooled HR, 1.28; 95% CI, 1.13-1.44; P < .001) but after adjustment for potential confounders, this association disappeared (pooled adjusted HR, 1.03; 95% CI, 0.91-1.17; P = .65). In the case-crossover study, we identified 84 841 individuals hospitalized with aortic aneurysm or dissection in Aurum (mean [SD] age, 75.5 [10.9]; 23 551 [27.8%] female) and 10 357 in GOLD (mean [SD] age, 75.6 [10.5]; 2809 [27.1%] female). Relative to nonuse, fluoroquinolone use was associated with an increase in hospitalization with aortic aneurysm or dissection, but no association was found relative to other antibiotics (vs cephalosporin pooled OR, 1.05; 95% CI, 0.87-1.27; vs trimethoprim, 0.89; 95% CI, 0.75-1.06; vs co-amoxiclav, 0.98; 95% CI, 0.82-1.18). Conclusions and Relevance: The results in this study suggest that estimates of association of fluoroquinolones with aortic aneurysm or dissection may be affected by confounding. When such confounding is accounted for, no association was evident, providing reassurance on the safety of fluoroquinolones with respect to aortic aneurysm or dissection.

Ethnic differences in the indirect effects of the COVID-19 pandemic on clinical monitoring and hospitalisations for non-COVID conditions in England: a population-based, observational cohort study using the OpenSAFELY platform.

Background: The COVID-19 pandemic disrupted healthcare and may have impacted ethnic inequalities in healthcare. We aimed to describe the impact of pandemic-related disruption on ethnic differences in clinical monitoring and hospital admissions for non-COVID conditions in England. Methods: In this population-based, observational cohort study we used primary care electronic health record data with linkage to hospital episode statistics data and mortality data within OpenSAFELY, a data analytics platform created, with approval of NHS England, to address urgent COVID-19 research questions. We included adults aged 18 years and over registered with a TPP practice between March 1, 2018, and April 30, 2022. We excluded those with missing age, sex, geographic region, or Index of Multiple Deprivation. We grouped ethnicity (exposure), into five categories: White, Asian, Black, Other, and Mixed. We used interrupted time-series regression to estimate ethnic differences in clinical monitoring frequency (blood pressure and Hba1c measurements, chronic obstructive pulmonary disease and asthma annual reviews) before and after March 23, 2020. We used multivariable Cox regression to quantify ethnic differences in hospitalisations related to diabetes, cardiovascular disease, respiratory disease, and mental health before and after March 23, 2020. Findings: Of 33,510,937 registered with a GP as of 1st January 2020, 19,064,019 were adults, alive and registered for at least 3 months, 3,010,751 met the exclusion criteria and 1,122,912 were missing ethnicity. This resulted in 14,930,356 adults with known ethnicity (92% of sample): 86.6% were White, 7.3% Asian, 2.6% Black, 1.4% Mixed ethnicity, and 2.2% Other ethnicities. Clinical monitoring did not return to pre-pandemic levels for any ethnic group. Ethnic differences were apparent pre-pandemic, except for diabetes monitoring, and remained unchanged, except for blood pressure monitoring in those with mental health conditions where differences narrowed during the pandemic. For those of Black ethnicity, there were seven additional admissions for diabetic ketoacidosis per month during the pandemic, and relative ethnic differences narrowed during the pandemic compared to the White ethnic group (Pre-pandemic hazard ratio (HR): 0.50, 95% confidence interval (CI) 0.41, 0.60, Pandemic HR: 0.75, 95% CI: 0.65, 0.87). There was increased admissions for heart failure during the pandemic for all ethnic groups, though highest in those of White ethnicity (heart failure risk difference: 5.4). Relatively, ethnic differences narrowed for heart failure admission in those of Asian (Pre-pandemic HR 1.56, 95% CI 1.49, 1.64, Pandemic HR 1.24, 95% CI 1.19, 1.29) and Black ethnicity (Pre-pandemic HR 1.41, 95% CI: 1.30, 1.53, Pandemic HR: 1.16, 95% CI 1.09, 1.25) compared with White ethnicity. For other outcomes the pandemic had minimal impact on ethnic differences. Interpretation: Our study suggests that ethnic differences in clinical monitoring and hospitalisations remained largely unchanged during the pandemic for most conditions. Key exceptions were hospitalisations for diabetic ketoacidosis and heart failure, which warrant further investigation to understand the causes. Funding: LSHTM COVID-19 Response Grant (DONAT15912).

Total sleep duration and daytime napping in relation to dementia detection risk: Results from the Million Women Study.

INTRODUCTION: There is inconsistent evidence on the associations of sleep duration and daytime napping with dementia risk. METHODS: In the Million Women Study, a total of 830,716 women (mean age, 60 years) were asked about sleep duration (<7, 7-8, >8 hours) and daytime napping (rarely/never, sometimes, usually) in median year 2001, and were followed for the first hospital record with any mention of dementia. Cox regression estimated dementia detection risk ratios (RRs) during 17-year follow-up in 5-year intervals. RESULTS: With 34,576 dementia cases, there was strong attenuation over follow-up in the RRs related to long sleep duration (>8 vs 7-8 hours) and usually napping (vs rarely/never). Short sleep duration was modestly, positively associated with dementia in the long term (RR = 1.08, 95% confidence interval [CI] 1.04-1.12). DISCUSSION: There was little evidence to suggest that long sleep duration and regular napping are associated with long-term dementia risk. Short sleep duration was modestly associated with dementia risk, but residual confounding cannot be excluded. HIGHLIGHTS: Long sleep duration was not associated with long-term dementia risk. Daytime napping was not associated with long-term dementia risk. There is some evidence for a small higher risk of dementia related to short sleep.

Methods for drug safety signal detection using routinely collected observational electronic health care data: A systematic review.

PURPOSE: Signal detection is a crucial step in the discovery of post-marketing adverse drug reactions. There is a growing interest in using routinely collected data to complement established spontaneous report analyses. This work aims to systematically review the methods for drug safety signal detection using routinely collected healthcare data and their performance, both in general and for specific types of drugs and outcomes. METHODS: We conducted a systematic review following the PRISMA guidelines, and registered a protocol in PROSPERO. MEDLINE, EMBASE, PubMed, Web of Science, Scopus, and the Cochrane Library were searched until July 13, 2021. RESULTS: The review included 101 articles, among which there were 39 methodological works, 25 performance assessment papers, and 24 observational studies. Methods included adaptations from those used with spontaneous reports, traditional epidemiological designs, methods specific to signal detection with real-world data. More recently, implementations of machine learning have been studied in the literature. Twenty-five studies evaluated method performances, 16 of them using the area under the curve (AUC) for a range of positive and negative controls as their main measure. Despite the likelihood that performance measurement could vary by drug-event pair, only 10 studies reported performance stratified by drugs and outcomes, in a heterogeneous manner. The replicability of the performance assessment results was limited due to lack of transparency in reporting and the lack of a gold standard reference set. CONCLUSIONS: A variety of methods have been described in the literature for signal detection with routinely collected data. No method showed superior performance in all papers and across all drugs and outcomes, performance assessment and reporting were heterogeneous. However, there is limited evidence that self-controlled designs, high dimensional propensity scores, and machine learning can achieve higher performances than other methods.

Proton pump inhibitors and myocardial infarction: an application of active comparators in a self-controlled case series.

BACKGROUND: Previous studies investigating potential cardiovascular adverse events of acid-suppressing drugs are susceptible to protopathic bias and confounding. We aimed to investigate the association between short-term risk of myocardial infarction (MI) and proton pump inhibitors (PPIs) using a self-controlled case series (SCCS) with an active comparator. METHODS: We conducted a SCCS using a population-wide database from Hong Kong from 2003-2014. Adult with ≥1 outpatient oral PPI prescription or H2 receptor antagonist (H2RA) and MI during the observation period were included. We used both simple ratio and effect modifier approaches to SCCS with active comparators to obtain comparator adjusted estimates. RESULTS: A total of 2802 and 1889 people with MI who had exposure to PPIs and H2RA were included respectively. We observed a higher risk of MI during days 1-14 following the start of PPI prescription (Incidence rate ratio (IRR): 2.30, 95% confidence interval (CI): 1.76-3.00) versus baseline. Similarly, we observed a higher risk of MI during days 1-14 following the start of H2RA prescription (IRR: 2.46, 95%CI: 1.92-3.16) versus baseline. In the novel SCCS analyses, comparator adjusted estimates were 0.93 (95%CI: 0.57-1.30) and 0.83 (95%CI: 0.58-1.20) during days 1-14 in simple ratio and effect modifier approach, respectively. CONCLUSIONS: We observed no difference in risk of MI associated with PPIs compared with baseline using H2RA as the active comparator. The elevated risk of MI associated with PPIs is likely due to protopathic bias. More studies are required to explore the feasibility of using active comparators in SCCS to address protopathic bias in addition to confounding.

Association between household composition and severe COVID-19 outcomes in older people by ethnicity: an observational cohort study using the OpenSAFELY platform.

BACKGROUND: Ethnic differences in the risk of severe COVID-19 may be linked to household composition. We quantified the association between household composition and risk of severe COVID-19 by ethnicity for older individuals. METHODS: With the approval of NHS England, we analysed ethnic differences in the association between household composition and severe COVID-19 in people aged 67 or over in England. We defined households by number of age-based generations living together, and used multivariable Cox regression stratified by location and wave of the pandemic and accounted for age, sex, comorbidities, smoking, obesity, housing density and deprivation. We included 2 692 223 people over 67 years in Wave 1 (1 February 2020-31 August 2020) and 2 731 427 in Wave 2 (1 September 2020-31 January 2021). RESULTS: Multigenerational living was associated with increased risk of severe COVID-19 for White and South Asian older people in both waves [e.g. Wave 2, 67+ living with three other generations vs 67+-year-olds only: White hazard ratio (HR) 1.61 95% CI 1.38-1.87, South Asian HR 1.76 95% CI 1.48-2.10], with a trend for increased risks of severe COVID-19 with increasing generations in Wave 2. There was also an increased risk of severe COVID-19 in Wave 1 associated with living alone for White (HR 1.35 95% CI 1.30-1.41), South Asian (HR 1.47 95% CI 1.18-1.84) and Other (HR 1.72 95% CI 0.99-2.97) ethnicities, an effect that persisted for White older people in Wave 2. CONCLUSIONS: Both multigenerational living and living alone were associated with severe COVID-19 in older adults. Older South Asian people are over-represented within multigenerational households in England, especially in the most deprived settings, whereas a substantial proportion of White older people live alone. The number of generations in a household, number of occupants, ethnicity and deprivation status are important considerations in the continued roll-out of COVID-19 vaccination and targeting of interventions for future pandemics.

Describing the population experiencing COVID-19 vaccine breakthrough following second vaccination in England: a cohort study from OpenSAFELY.

BACKGROUND: While the vaccines against COVID-19 are highly effective, COVID-19 vaccine breakthrough is possible despite being fully vaccinated. With SARS-CoV-2 variants still circulating, describing the characteristics of individuals who have experienced COVID-19 vaccine breakthroughs could be hugely important in helping to determine who may be at greatest risk. METHODS: With the approval of NHS England, we conducted a retrospective cohort study using routine clinical data from the OpenSAFELY-TPP database of fully vaccinated individuals, linked to secondary care and death registry data and described the characteristics of those experiencing COVID-19 vaccine breakthroughs. RESULTS: As of 1st November 2021, a total of 15,501,550 individuals were identified as being fully vaccinated against COVID-19, with a median follow-up time of 149 days (IQR: ​107-179). From within this population, a total of 579,780 (<4%) individuals reported a positive SARS-CoV-2 test. For every 1000 years of patient follow-up time, the corresponding incidence rate (IR) was 98.06 (95% CI 97.93-98.19). There were 28,580 COVID-19-related hospital admissions, 1980 COVID-19-related critical care admissions and 6435 COVID-19-related deaths; corresponding IRs 4.77 (95% CI 4.74-4.80), 0.33 (95% CI 0.32-0.34) and 1.07 (95% CI 1.06-1.09), respectively. The highest rates of breakthrough COVID-19 were seen in those in care homes and in patients with chronic kidney disease, dialysis, transplant, haematological malignancy or who were immunocompromised. CONCLUSIONS: While the majority of COVID-19 vaccine breakthrough cases in England were mild, some differences in rates of breakthrough cases have been identified in several clinical groups. While it is important to note that these findings are simply descriptive and cannot be used to answer why certain groups have higher rates of COVID-19 breakthrough than others, the emergence of the Omicron variant of COVID-19 coupled with the number of positive SARS-CoV-2 tests still occurring is concerning and as numbers of fully vaccinated (and boosted) individuals increases and as follow-up time lengthens, so too will the number of COVID-19 breakthrough cases. Additional analyses, to assess vaccine waning and rates of breakthrough COVID-19 between different variants, aimed at identifying individuals at higher risk, are needed.

Comparative effectiveness of ChAdOx1 versus BNT162b2 covid-19 vaccines in health and social care workers in England: cohort study using OpenSAFELY.

OBJECTIVE: To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and the ChAdOx1 (Oxford-AstraZeneca) covid-19 vaccines against infection and covid-19 disease in health and social care workers. DESIGN: Cohort study, emulating a comparative effectiveness trial, on behalf of NHS England. SETTING: Linked primary care, hospital, and covid-19 surveillance records available within the OpenSAFELY-TPP research platform, covering a period when the SARS-CoV-2 Alpha variant was dominant. PARTICIPANTS: 317 341 health and social care workers vaccinated between 4 January and 28 February 2021, registered with a general practice using the TPP SystmOne clinical information system in England, and not clinically extremely vulnerable. INTERVENTIONS: Vaccination with either BNT162b2 or ChAdOx1 administered as part of the national covid-19 vaccine roll-out. MAIN OUTCOME MEASURES: Recorded SARS-CoV-2 positive test, or covid-19 related attendance at an accident and emergency (A&E) department or hospital admission occurring within 20 weeks of receipt of the first vaccine dose. RESULTS: Over the duration of 118 771 person-years of follow-up there were 6962 positive SARS-CoV-2 tests, 282 covid-19 related A&E attendances, and 166 covid-19 related hospital admissions. The cumulative incidence of each outcome was similar for both vaccines during the first 20 weeks after vaccination. The cumulative incidence of recorded SARS-CoV-2 infection 20 weeks after first-dose vaccination with BNT162b2 was 21.7 per 1000 people (95% confidence interval 20.9 to 22.4) and with ChAdOx1 was 23.7 (21.8 to 25.6), representing a difference of 2.04 per 1000 people (0.04 to 4.04). The difference in the cumulative incidence per 1000 people of covid-19 related A&E attendance at 20 weeks was 0.06 per 1000 people (95% CI -0.31 to 0.43). For covid-19 related hospital admission, this difference was 0.11 per 1000 people (-0.22 to 0.44). CONCLUSIONS: In this cohort of healthcare workers where we would not anticipate vaccine type to be related to health status, we found no substantial differences in the incidence of SARS-CoV-2 infection or covid-19 disease up to 20 weeks after vaccination. Incidence dropped sharply at 3-4 weeks after vaccination, and there were few covid-19 related hospital attendance and admission events after this period. This is in line with expected onset of vaccine induced immunity and suggests strong protection against Alpha variant covid-19 disease for both vaccines in this relatively young and healthy population of healthcare workers.

Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune-modifying therapies: a nationwide cohort study in the OpenSAFELY platform.

Background: The risk of severe COVID-19 outcomes in people with immune-mediated inflammatory diseases and on immune-modifying drugs might not be fully mediated by comorbidities and might vary by factors such as ethnicity. We aimed to assess the risk of severe COVID-19 in adults with immune-mediated inflammatory diseases and in those on immune-modifying therapies. Methods: We did a cohort study, using OpenSAFELY (an analytics platform for electronic health records) and TPP (a software provider for general practitioners), analysing routinely collected primary care data linked to hospital admission, death, and previously unavailable hospital prescription data. We included people aged 18 years or older on March 1, 2020, who were registered with TPP practices with at least 12 months of primary care records before March, 2020. We used Cox regression (adjusting for confounders and mediators) to estimate hazard ratios (HRs) comparing the risk of COVID-19-related death, critical care admission or death, and hospital admission (from March 1 to Sept 30, 2020) in people with immune-mediated inflammatory diseases compared with the general population, and in people with immune-mediated inflammatory diseases on targeted immune-modifying drugs (eg, biologics) compared with those on standard systemic treatment (eg, methotrexate). Findings: We identified 17 672 065 adults; 1 163 438 adults (640 164 [55·0%] women and 523 274 [45·0%] men, and 827 457 [71·1%] of White ethnicity) had immune-mediated inflammatory diseases, and 16 508 627 people (8 215 020 [49·8%] women and 8 293 607 [50·2%] men, and 10 614 096 [64·3%] of White ethnicity) were included as the general population. Of 1 163 438 adults with immune-mediated inflammatory diseases, 19 119 (1·6%) received targeted immune-modifying therapy and 181 694 (15·6%) received standard systemic therapy. Compared with the general population, adults with immune-mediated inflammatory diseases had an increased risk of COVID-19-related death after adjusting for confounders (age, sex, deprivation, and smoking status; HR 1·23, 95% CI 1·20-1·27) and further adjusting for mediators (body-mass index [BMI], cardiovascular disease, diabetes, and current glucocorticoid use; 1·15, 1·11-1·18). Adults with immune-mediated inflammatory diseases also had an increased risk of COVID-19-related critical care admission or death (confounder-adjusted HR 1·24, 95% CI 1·21-1·28; mediator-adjusted 1·16, 1·12-1·19) and hospital admission (confounder-adjusted 1·32, 1·29-1·35; mediator-adjusted 1·20, 1·17-1·23). In post-hoc analyses, the risk of severe COVID-19 outcomes in people with immune-mediated inflammatory diseases was higher in non-White ethnic groups than in White ethnic groups (as it was in the general population). We saw no evidence of increased COVID-19-related death in adults on targeted, compared with those on standard systemic, therapy after adjusting for confounders (age, sex, deprivation, BMI, immune-mediated inflammatory diseases [bowel, joint, and skin], cardiovascular disease, cancer [excluding non-melanoma skin cancer], stroke, and diabetes (HR 1·03, 95% CI 0·80-1·33), and after additionally adjusting for current glucocorticoid use (1·01, 0·78-1·30). There was no evidence of increased COVID-19-related death in adults prescribed tumour necrosis factor inhibitors, interleukin (IL)-12/IL­23 inhibitors, IL-17 inhibitors, IL-6 inhibitors, or Janus kinase inhibitors compared with those on standard systemic therapy. Rituximab was associated with increased COVID-19-related death (HR 1·68, 95% CI 1·11-2·56), with some attenuation after excluding people with haematological malignancies or organ transplants (1·54, 0·95-2·49). Interpretation: COVID-19 deaths and hospital admissions were higher in people with immune-mediated inflammatory diseases. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune-modifying drugs for immune-mediated inflammatory diseases compared with those on standard systemic therapy. Funding: UK Medical Research Council, NIHR Biomedical Research Centre at King's College London and Guy's and St Thomas' NHS Foundation Trust, and Wellcome Trust.

Association between oral anticoagulants and COVID-19-related outcomes: a population-based cohort study.

BACKGROUND: Early evidence has shown that anticoagulant reduces the risk of thrombotic events in those infected with COVID-19. However, evidence of the role of routinely prescribed oral anticoagulants (OACs) in COVID-19 outcomes is limited. AIM: To investigate the association between OACs and COVID-19 outcomes in those with atrial fibrillation and a CHA2DS2-VASc score of 2. DESIGN AND SETTING: On behalf of NHS England, a population-based cohort study was conducted. METHOD: The study used primary care data and pseudonymously-linked SARS-CoV-2 antigen testing data, hospital admissions, and death records from England. Cox regression was used to estimate hazard ratios (HRs) for COVID-19 outcomes comparing people with current OAC use versus non-use, accounting for age, sex, comorbidities, other medications, deprivation, and general practice. RESULTS: Of 71 103 people with atrial fibrillation and a CHA2DS2-VASc score of 2, there were 52 832 current OAC users and 18 271 non-users. No difference in risk of being tested for SARS-CoV-2 was associated with current use (adjusted HR [aHR] 0.99, 95% confidence interval [CI] = 0.95 to 1.04) versus non-use. A lower risk of testing positive for SARS-CoV-2 (aHR 0.77, 95% CI = 0.63 to 0.95) and a marginally lower risk of COVID-19-related death (aHR, 0.74, 95% CI = 0.53 to 1.04) were associated with current use versus non-use. CONCLUSION: Among those at low baseline stroke risk, people receiving OACs had a lower risk of testing positive for SARS-CoV-2 and severe COVID-19 outcomes than non-users; this might be explained by a causal effect of OACs in preventing severe COVID-19 outcomes or unmeasured confounding, including more cautious behaviours leading to reduced infection risk.

Effects of ACE inhibitors and angiotensin receptor blockers: protocol for a UK cohort study using routinely collected electronic health records with validation against the ONTARGET trial.

INTRODUCTION: Cardiovascular disease is a leading cause of death globally, responsible for nearly 18 million deaths worldwide in 2017. Medications to reduce the risk of cardiovascular events are prescribed based on evidence from clinical trials which explore treatment effects in an indicated sample of the general population. However, these results may not be fully generalisable because of trial eligibility criteria that generally restrict to younger patients with fewer comorbidities. Therefore, evidence of effectiveness of medications for groups underrepresented in clinical trials such as those aged ≥75 years, from ethnic minority backgrounds or with low kidney function may be limited.Using individual anonymised data from the Ongoing Telmisartan Alone and the Ramipril Global Endpoint Trial (ONTARGET) trial, in collaboration with the original trial investigators, we aim to investigate clinical trial replicability within a real-world setting in the area of cardiovascular disease. If the original trial results are replicable, we will estimate treatment effects and risk in groups underrepresented and excluded from the original clinical trial. METHODS AND ANALYSIS: We will develop a cohort analogous to the ONTARGET trial within the Clinical Practice Research Datalink between 1 January 2001 and 31 July 2019 using the trial eligibility criteria and propensity score matching. The primary outcome is a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for congestive heart failure. If results from the cohort study fall within pre-specified limits, we will expand the cohort to include under represented and excluded groups. ETHICS AND DISSEMINATION: Ethical approval has been granted by the London School of Hygiene & Tropical Medicine Ethics Committee (Ref: 22658). The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency (protocol no. 20_012). Access to the individual patient data from the ONTARGET trial was obtained by the trial investigators. Findings will be submitted to peer-reviewed journals and presented at conferences.