Pooling of primary care electronic health record (EHR) data on Huntington's disease (HD) and cancer: establishing comparability of two large UK databases.

OBJECTIVES: To explore whether UK primary care databases arising from two different software systems can be feasibly combined, by comparing rates of Huntington's disease (HD, which is rare) and 14 common cancers in the two databases, as well as characteristics of people with these conditions. DESIGN: Descriptive study. SETTING: Primary care electronic health records from Clinical Practice Research Datalink (CPRD) GOLD and CPRD Aurum databases, with linked hospital admission and death registration data. PARTICIPANTS: 4986 patients with HD and 1 294 819 with an incident cancer between 1990 and 2019. PRIMARY AND SECONDARY OUTCOME MEASURES: Incidence and prevalence of HD by calendar period, age group and region, and annual age-standardised incidence of 14 common cancers in each database, and in a subset of 'overlapping' practices which contributed to both databases. Characteristics of patients with HD or incident cancer: medical history, recent prescribing, healthcare contacts and database follow-up. RESULTS: Incidence and prevalence of HD were slightly higher in CPRD GOLD than CPRD Aurum, but with similar trends over time. Cancer incidence in the two databases differed between 1990 and 2000, but converged and was very similar thereafter. Participants in each database were most similar in terms of medical history (median standardised difference, MSD 0.03 (IQR 0.01-0.03)), recent prescribing (MSD 0.06 (0.03-0.10)) and demographics and general health variables (MSD 0.05 (0.01-0.09)). Larger differences were seen for healthcare contacts (MSD 0.27 (0.10-0.41)), and database follow-up (MSD 0.39 (0.19-0.56)). CONCLUSIONS: Differences in cancer incidence trends between 1990 and 2000 may relate to use of a practice-level data quality filter (the 'up-to-standard' date) in CPRD GOLD only. As well as the impact of data curation methods, differences in underlying data models can make it more challenging to define exactly equivalent clinical concepts in each database. Researchers should be aware of these potential sources of variability when planning combined database studies and interpreting results.

Five-alpha reductase inhibitors and risk of prostate cancer among men with benign prostatic hyperplasia: A historical cohort study using primary care data.

Background: Five-alpha reductase inhibitors (5ARIs) are used in the management of benign prostatic hyperplasia (BPH). 5ARIs prevent the conversion of testosterone to dihydrotestosterone, which is important in prostate development. It has been suggested that 5ARIs can be used a chemopreventative agent for prostate cancer. The aim of this study was to assess the risk of prostate cancer associated with 5ARI use among men with BPH. Methods: Using Clinical Practice Research Datalink (CPRD) from 1992 to 2011 in UK, prostate cancer risk was retrospectively compared in men with a new diagnosis of BPH, with no history of prostate cancer who were treated with 5ARIs, to men treated with alpha blockers (ABs) and those given no pharmacological treatment. Incidence rate of prostate cancer was calculated by treatment group; the association between BPH treatment group and prostate cancer was estimated by a multivariate Cox model. Results: 77,494 men with newly diagnosed BPH were included. The crude incidence rate of prostate cancer was 892.4 cases per 100,000 person-years amongst those treated with 5ARIs, compared with 1209.0 and 1542.9 in those treated with ABs and untreated individuals, respectively. The HR adjusted for potential confounders was 0.79 (0.72-0.86) for 5ARI vs ABs and 0.72 (0.66-0.79) for 5ARI vs untreated. After excluding the first year after BPH diagnosis, adjusted HRs attenuated to 0.87 (0.79-0.97) for 5ARI vs ABs and 0.97 (0.87-1.08) for 5ARI vs untreated. Conclusion: Among men diagnosed with BPH, we found evidence of lower risks of subsequent prostate cancer in those treated with 5ARIs, but this appeared to be driven by cases diagnosed within a year of BPH, possibly reflecting prevalent prostate cancers that were initially misdiagnosed. After excluding the first year after BPH diagnosis, there was little evidence of a reduced prostate cancer risk in those taking 5ARIs.

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.

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.

Safety of COVID-19 vaccination and acute neurological events: A self-controlled case series in England using the OpenSAFELY platform.

INTRODUCTION: We investigated the potential association of COVID-19 vaccination with three acute neurological events: Guillain-Barré syndrome (GBS), transverse myelitis and Bell's palsy. METHODS: With the approval of NHS England we analysed primary care data from >17 million patients in England linked to emergency care, hospital admission and mortality records in the OpenSAFELY platform. Separately for each vaccine brand, we used a self-controlled case series design to estimate the incidence rate ratio for each outcome in the period following vaccination (4-42 days for GBS, 4-28 days for transverse myelitis and Bell's palsy) compared to a within-person baseline, using conditional Poisson regression. RESULTS: Among 7,783,441 ChAdOx1 vaccinees, there was an increased rate of GBS (N = 517; incidence rate ratio 2·85; 95% CI2·33-3·47) and Bell's palsy (N = 5,350; 1·39; 1·27-1·53) following a first dose of ChAdOx1 vaccine, corresponding to 11.0 additional cases of GBS and 17.9 cases of Bell's palsy per 1 million vaccinees if causal. For GBS this applied to the first, but not the second, dose. There was no clear evidence of an association of ChAdOx1 vaccination with transverse myelitis (N = 199; 1·51; 0·96-2·37). Among 5,729,152 BNT162b2 vaccinees, there was no evidence of any association with GBS (N = 283; 1·09; 0·75-1·57), transverse myelitis (N = 109; 1·62; 0·86-3·03) or Bell's palsy (N = 3,609; 0·89; 0·76-1·03). Among 255,446 mRNA-1273 vaccine recipients there was no evidence of an association with Bell's palsy (N = 78; 0·88, 0·32-2·42). CONCLUSIONS: COVID-19 vaccines save lives, but it is important to understand rare adverse events. We observed a short-term increased rate of Guillain-Barré syndrome and Bell's palsy after first dose of ChAdOx1 vaccine. The absolute risk, assuming a causal effect attributable to vaccination, was low.

Overall and cause-specific hospitalisation and death after COVID-19 hospitalisation in England: A cohort study using linked primary care, secondary care, and death registration data in the OpenSAFELY platform.

BACKGROUND: There is concern about medium to long-term adverse outcomes following acute Coronavirus Disease 2019 (COVID-19), but little relevant evidence exists. We aimed to investigate whether risks of hospital admission and death, overall and by specific cause, are raised following discharge from a COVID-19 hospitalisation. METHODS AND FINDINGS: With the approval of NHS-England, we conducted a cohort study, using linked primary care and hospital data in OpenSAFELY to compare risks of hospital admission and death, overall and by specific cause, between people discharged from COVID-19 hospitalisation (February to December 2020) and surviving at least 1 week, and (i) demographically matched controls from the 2019 general population; and (ii) people discharged from influenza hospitalisation in 2017 to 2019. We used Cox regression adjusted for age, sex, ethnicity, obesity, smoking status, deprivation, and comorbidities considered potential risk factors for severe COVID-19 outcomes. We included 24,673 postdischarge COVID-19 patients, 123,362 general population controls, and 16,058 influenza controls, followed for ≤315 days. COVID-19 patients had median age of 66 years, 13,733 (56%) were male, and 19,061 (77%) were of white ethnicity. Overall risk of hospitalisation or death (30,968 events) was higher in the COVID-19 group than general population controls (fully adjusted hazard ratio [aHR] 2.22, 2.14 to 2.30, p < 0.001) but slightly lower than the influenza group (aHR 0.95, 0.91 to 0.98, p = 0.004). All-cause mortality (7,439 events) was highest in the COVID-19 group (aHR 4.82, 4.48 to 5.19 versus general population controls [p < 0.001] and 1.74, 1.61 to 1.88 versus influenza controls [p < 0.001]). Risks for cause-specific outcomes were higher in COVID-19 survivors than in general population controls and largely similar or lower in COVID-19 compared with influenza patients. However, COVID-19 patients were more likely than influenza patients to be readmitted or die due to their initial infection or other lower respiratory tract infection (aHR 1.37, 1.22 to 1.54, p < 0.001) and to experience mental health or cognitive-related admission or death (aHR 1.37, 1.02 to 1.84, p = 0.039); in particular, COVID-19 survivors with preexisting dementia had higher risk of dementia hospitalisation or death (age- and sex-adjusted HR 2.47, 1.37 to 4.44, p = 0.002). Limitations of our study were that reasons for hospitalisation or death may have been misclassified in some cases due to inconsistent use of codes, and we did not have data to distinguish COVID-19 variants. CONCLUSIONS: In this study, we observed that people discharged from a COVID-19 hospital admission had markedly higher risks for rehospitalisation and death than the general population, suggesting a substantial extra burden on healthcare. Most risks were similar to those observed after influenza hospitalisations, but COVID-19 patients had higher risks of all-cause mortality, readmission or death due to the initial infection, and dementia death, highlighting the importance of postdischarge monitoring.

Unicompartmental compared with total knee replacement for patients with multimorbidities: a cohort study using propensity score stratification and inverse probability weighting.

BACKGROUND: Although routine NHS data potentially include all patients, confounding limits their use for causal inference. Methods to minimise confounding in observational studies of implantable devices are required to enable the evaluation of patients with severe systemic morbidity who are excluded from many randomised controlled trials. OBJECTIVES: Stage 1 - replicate the Total or Partial Knee Arthroplasty Trial (TOPKAT), a surgical randomised controlled trial comparing unicompartmental knee replacement with total knee replacement using propensity score and instrumental variable methods. Stage 2 - compare the risk benefits and cost-effectiveness of unicompartmental knee replacement with total knee replacement surgery in patients with severe systemic morbidity who would have been ineligible for TOPKAT using the validated methods from stage 1. DESIGN: This was a cohort study. SETTING: Data were obtained from the National Joint Registry database and linked to hospital inpatient (Hospital Episode Statistics) and patient-reported outcome data. PARTICIPANTS: Stage 1 - people undergoing unicompartmental knee replacement surgery or total knee replacement surgery who met the TOPKAT eligibility criteria. Stage 2 - participants with an American Society of Anesthesiologists grade of ≥ 3. INTERVENTION: The patients were exposed to either unicompartmental knee replacement surgery or total knee replacement surgery. MAIN OUTCOME MEASURES: The primary outcome measure was the postoperative Oxford Knee Score. The secondary outcome measures were 90-day postoperative complications (venous thromboembolism, myocardial infarction and prosthetic joint infection) and 5-year revision risk and mortality. The main outcome measures for the health economic analysis were health-related quality of life (EuroQol-5 Dimensions) and NHS hospital costs. RESULTS: In stage 1, propensity score stratification and inverse probability weighting replicated the results of TOPKAT. Propensity score adjustment, propensity score matching and instrumental variables did not. Stage 2 included 2256 unicompartmental knee replacement patients and 57,682 total knee replacement patients who had severe comorbidities, of whom 145 and 23,344 had linked Oxford Knee Scores, respectively. A statistically significant but clinically irrelevant difference favouring unicompartmental knee replacement was observed, with a mean postoperative Oxford Knee Score difference of < 2 points using propensity score stratification; no significant difference was observed using inverse probability weighting. Unicompartmental knee replacement more than halved the risk of venous thromboembolism [relative risk 0.33 (95% confidence interval 0.15 to 0.74) using propensity score stratification; relative risk 0.39 (95% confidence interval 0.16 to 0.96) using inverse probability weighting]. Unicompartmental knee replacement was not associated with myocardial infarction or prosthetic joint infection using either method. In the long term, unicompartmental knee replacement had double the revision risk of total knee replacement [hazard ratio 2.70 (95% confidence interval 2.15 to 3.38) using propensity score stratification; hazard ratio 2.60 (95% confidence interval 1.94 to 3.47) using inverse probability weighting], but half of the mortality [hazard ratio 0.52 (95% confidence interval 0.36 to 0.74) using propensity score stratification; insignificant effect using inverse probability weighting]. Unicompartmental knee replacement had lower costs and higher quality-adjusted life-year gains than total knee replacement for stage 2 participants. LIMITATIONS: Although some propensity score methods successfully replicated TOPKAT, unresolved confounding may have affected stage 2. Missing Oxford Knee Scores may have led to information bias. CONCLUSIONS: Propensity score stratification and inverse probability weighting successfully replicated TOPKAT, implying that some (but not all) propensity score methods can be used to evaluate surgical innovations and implantable medical devices using routine NHS data. Unicompartmental knee replacement was safer and more cost-effective than total knee replacement for patients with severe comorbidity and should be considered the first option for suitable patients. FUTURE WORK: Further research is required to understand the performance of propensity score methods for evaluating surgical innovations and implantable devices. TRIAL REGISTRATION: This trial is registered as EUPAS17435. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 66. See the NIHR Journals Library website for further project information.

We compared the risks and benefits of partial and total knee replacements in NHS patients with a complex medical history who would normally be excluded from randomised trials on this topic. We used information that was collected during hospital appointments for people who had a knee replacement between 2009 and 2016. It is difficult to directly compare the two groups because each individual patient has a different medical history. We tested advanced statistical methods to account for these differences. In stage 1, we showed that some of these advanced statistical methods could replicate the results of a recently published surgical trial using routine data from the NHS. We compared patients in the trial with similar patients who were operated on in the NHS. Three of the proposed methods showed results similar to those obtained from the Total or Partial Knee Arthroplasty Trial (TOPKAT). In stage 2, we used the successful methods from stage 1 to study the risks, benefits and costs of partial and total knee replacement surgery in patients with complex medical histories. Two of the statistical methods found that patients who had a partial knee replacement had less self-reported pain and better function after surgery than patients who had a total knee replacement. All three methods found that partial knee replacement was safer, was associated with a lower risk of blood clots (a known complication of knee surgery) and had lower mortality over 5 years. However, patients who had a partial knee replacement were twice as likely as those with a total knee replacement to need a second surgery within 5 years. We found that partial knee replacements were less costly to the NHS and were associated with better overall quality of life for patients than total knee replacement.

Association between warfarin and COVID-19-related outcomes compared with direct oral anticoagulants: population-based cohort study.

BACKGROUND: Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant, it acts by antagonising vitamin K, which is low in patients with severe COVID-19. To date, the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking. METHODS: On behalf of NHS England, we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the OpenSAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data, hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding. RESULTS: A total of 92,339 warfarin users and 280,407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2, HR 0.73 (95% CI 0.68-0.79); COVID-19-related hospital admission, HR 0.75 (95% CI 0.68-0.83); COVID-19-related deaths, HR 0.74 (95% CI 0.66-0.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2, HR 0.80 (95% CI 0.79-0.81); non-COVID-19 deaths, HR 0.79 (95% CI 0.76-0.83)]. CONCLUSIONS: Overall, this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease.

Factors associated with deaths due to COVID-19 versus other causes: population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.

BACKGROUND: Mortality from COVID-19 shows a strong relationship with age and pre-existing medical conditions, as does mortality from other causes. We aimed to investigate how specific factors are differentially associated with COVID-19 mortality as compared to mortality from causes other than COVID-19. METHODS: Working on behalf of NHS England, we carried out a cohort study within the OpenSAFELY platform. Primary care data from England were linked to national death registrations. We included all adults (aged ≥18 years) in the database on 1st February 2020 and with >1 year of continuous prior registration; the cut-off date for deaths was 9th November 2020. Associations between individual-level characteristics and COVID-19 and non-COVID deaths, classified according to the presence of a COVID-19 code as the underlying cause of death on the death certificate, were estimated by fitting age- and sex-adjusted logistic models for these two outcomes. FINDINGS: 17,456,515 individuals were included. 17,063 died from COVID-19 and 134,316 from other causes. Most factors associated with COVID-19 death were similarly associated with non-COVID death, but the magnitudes of association differed. Older age was more strongly associated with COVID-19 death than non-COVID death (e.g. ORs 40.7 [95% CI 37.7-43.8] and 29.6 [28.9-30.3] respectively for ≥80 vs 50-59 years), as was male sex, deprivation, obesity, and some comorbidities. Smoking, history of cancer and chronic liver disease had stronger associations with non-COVID than COVID-19 death. All non-white ethnic groups had higher odds than white of COVID-19 death (OR for Black: 2.20 [1.96-2.47], South Asian: 2.33 [2.16-2.52]), but lower odds than white of non-COVID death (Black: 0.88 [0.83-0.94], South Asian: 0.78 [0.75-0.81]). INTERPRETATION: Similar associations of most individual-level factors with COVID-19 and non-COVID death suggest that COVID-19 largely multiplies existing risks faced by patients, with some notable exceptions. Identifying the unique factors contributing to the excess COVID-19 mortality risk among non-white groups is a priority to inform efforts to reduce deaths from COVID-19. FUNDING: Wellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, Health Data Research UK.

UK prevalence of underlying conditions which increase the risk of severe COVID-19 disease: a point prevalence study using electronic health records.

BACKGROUND: Characterising the size and distribution of the population at risk of severe COVID-19 is vital for effective policy and planning. Older age, and underlying health conditions, are associated with higher risk of death from COVID-19. This study aimed to describe the population at risk of severe COVID-19 due to underlying health conditions across the United Kingdom. METHODS: We used anonymised electronic health records from the Clinical Practice Research Datalink GOLD to estimate the point prevalence on 5 March 2019 of the at-risk population following national guidance. Prevalence for any risk condition and for each individual condition is given overall and stratified by age and region with binomial exact confidence intervals. We repeated the analysis on 5 March 2014 for full regional representation and to describe prevalence of underlying health conditions in pregnancy. We additionally described the population of cancer survivors, and assessed the value of linked secondary care records for ascertaining COVID-19 at-risk status. RESULTS: On 5 March 2019, 24.4% of the UK population were at risk due to a record of at least one underlying health condition, including 8.3% of school-aged children, 19.6% of working-aged adults, and 66.2% of individuals aged 70 years or more. 7.1% of the population had multimorbidity. The size of the at-risk population was stable over time comparing 2014 to 2019, despite increases in chronic liver disease and diabetes and decreases in chronic kidney disease and current asthma. Separately, 1.6% of the population had a new diagnosis of cancer in the past 5 y. CONCLUSIONS: The population at risk of severe COVID-19 (defined as either aged ≥70 years, or younger with an underlying health condition) comprises 18.5 million individuals in the UK, including a considerable proportion of school-aged and working-aged individuals. Our national estimates broadly support the use of Global Burden of Disease modelled estimates in other countries. We provide age- and region- stratified prevalence for each condition to support effective modelling of public health interventions and planning of vaccine resource allocation. The high prevalence of health conditions among older age groups suggests that age-targeted vaccination strategies may efficiently target individuals at higher risk of severe COVID-19.

Proton pump inhibitors and risk of all-cause and cause-specific mortality: A cohort study.

AIM: To investigate the association between proton pump inhibitors (PPIs) and both all-cause and cause-specific mortality. METHODS: We conducted a cohort study using the UK Clinical Practice Research Datalink GOLD database. We compared 733 885 new users of PPIs to 124 410 new users of H2 receptor antagonists (H2Ras). In a secondary analysis we compared 689 602 PPI new users to 1 361 245 nonusers of acid suppression therapy matched on age, sex and calendar year. Hazard ratios for all-cause and cause-specific mortality were estimated using propensity score (PS) weighted Cox models. RESULTS: PPI prescription was associated with increased risk of all-cause mortality, with hazard ratios decreasing considerably by increasing adjustment (unadjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.62-1.69; PS-weighted HR 1.38, 95% CI 1.33-1.44; high-dimensional PS-weighted HR 1.31, 95% CI 1.26-1.37). Short-term associations were observed with mortality from causes where a causal short-term association is unexpected (eg, lung cancer mortality: PS-weighted HR at 6 months 1.77, 95% CI 1.39-2.25). Adjusted hazard ratios were substantially higher when compared to nonusers (PS-weighted HR all-cause mortality 1.96, 95% CI 1.94-1.99) rather than H2RA users. CONCLUSIONS: PPI prescription was strongly associated with all-cause and cause-specific mortality. However, the change in hazard ratios (a) by increasing adjustment and (b) between comparator groups indicates that residual confounding is likely to explain the association between poor health outcomes and PPI use, and fully accounting for this using observational data may not be possible.

HIV infection and COVID-19 death: a population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.

BACKGROUND: Whether HIV infection is associated with risk of death due to COVID-19 is unclear. We aimed to investigate this association in a large-scale population-based study in England. METHODS: We did a retrospective cohort study. Working on behalf of NHS England, we used the OpenSAFELY platform to analyse routinely collected electronic primary care data linked to national death registrations. We included all adults (aged ≥18 years) alive and in follow-up on Feb 1, 2020, and with at least 1 year of continuous registration with a general practitioner before this date. People with a primary care record for HIV infection were compared with people without HIV. The outcome was COVID-19 death, defined as the presence of International Classification of Diseases 10 codes U07.1 or U07.2 anywhere on the death certificate. Cox regression models were used to estimate the association between HIV infection and COVID-19 death; they were initially adjusted for age and sex, then we added adjustment for index of multiple deprivation and ethnicity, and then for a broad range of comorbidities. Interaction terms were added to assess effect modification by age, sex, ethnicity, comorbidities, and calendar time. RESULTS: 17 282 905 adults were included, of whom 27 480 (0·16%) had HIV recorded. People living with HIV were more likely to be male, of Black ethnicity, and from a more deprived geographical area than the general population. 14 882 COVID-19 deaths occurred during the study period, with 25 among people with HIV. People living with HIV had higher risk of COVID-19 death than those without HIV after adjusting for age and sex: hazard ratio (HR) 2·90 (95% CI 1·96-4·30; p<0·0001). The association was attenuated, but risk remained high, after adjustment for deprivation, ethnicity, smoking and obesity: adjusted HR 2·59 (95% CI 1·74-3·84; p<0·0001). There was some evidence that the association was larger among people of Black ethnicity: HR 4·31 (95% CI 2·42-7·65) versus 1·84 (1·03-3·26) in non-Black individuals (p-interaction=0·044). INTERPRETATION: People with HIV in the UK seem to be at increased risk of COVID-19 mortality. Targeted policies should be considered to address this raised risk as the pandemic response evolves. FUNDING: Wellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, Health Data Research UK.

Factors associated with COVID-19-related death using OpenSAFELY.

Coronavirus disease 2019 (COVID-19) has rapidly affected mortality worldwide1. There is unprecedented urgency to understand who is most at risk of severe outcomes, and this requires new approaches for the timely analysis of large datasets. Working on behalf of NHS England, we created OpenSAFELY-a secure health analytics platform that covers 40% of all patients in England and holds patient data within the existing data centre of a major vendor of primary care electronic health records. Here we used OpenSAFELY to examine factors associated with COVID-19-related death. Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19-related deaths. COVID-19-related death was associated with: being male (hazard ratio (HR) 1.59 (95% confidence interval 1.53-1.65)); greater age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared with people of white ethnicity, Black and South Asian people were at higher risk, even after adjustment for other factors (HR 1.48 (1.29-1.69) and 1.45 (1.32-1.58), respectively). We have quantified a range of clinical factors associated with COVID-19-related death in one of the largest cohort studies on this topic so far. More patient records are rapidly being added to OpenSAFELY, we will update and extend our results regularly.

Association of BMI with overall and cause-specific mortality: a population-based cohort study of 3·6 million adults in the UK.

BACKGROUND: BMI is known to be strongly associated with all-cause mortality, but few studies have been large enough to reliably examine associations between BMI and a comprehensive range of cause-specific mortality outcomes. METHODS: In this population-based cohort study, we used UK primary care data from the Clinical Practice Research Datalink (CPRD) linked to national mortality registration data and fitted adjusted Cox regression models to examine associations between BMI and all-cause mortality, and between BMI and a comprehensive range of cause-specific mortality outcomes (recorded by International Classification of Diseases, 10th revision [ICD-10] codes). We included all individuals with BMI data collected at age 16 years and older and with subsequent follow-up time available. Follow-up began at whichever was the latest of: start of CPRD research-standard follow up, the 5-year anniversary of the first BMI record, or on Jan 1, 1998 (start date for death registration data); follow-up ended at death or on March 8, 2016. Fully adjusted models were stratified by sex and adjusted for baseline age, smoking, alcohol use, diabetes, index of multiple deprivation, and calendar period. Models were fitted in both never-smokers only and the full study population. We also did an extensive range of sensitivity analyses. The expected age of death for men and women aged 40 years at baseline, by BMI category, was estimated from a Poisson model including BMI, age, and sex. FINDINGS: 3 632 674 people were included in the full study population; the following results are from the analysis of never-smokers, which comprised 1 969 648 people and 188 057 deaths. BMI had a J-shaped association with overall mortality; the estimated hazard ratio per 5 kg/m2 increase in BMI was 0·81 (95% CI 0·80-0·82) below 25 kg/m2 and 1·21 (1·20-1·22) above this point. BMI was associated with all cause of death categories except for transport-related accidents, but the shape of the association varied. Most causes, including cancer, cardiovascular diseases, and respiratory diseases, had a J-shaped association with BMI, with lowest risk occurring in the range 21-25 kg/m2. For mental and behavioural, neurological, and accidental (non-transport-related) causes, BMI was inversely associated with mortality up to 24-27 kg/m2, with little association at higher BMIs; for deaths from self-harm or interpersonal violence, an inverse linear association was observed. Associations between BMI and mortality were stronger at younger ages than at older ages, and the BMI associated with lowest mortality risk was higher in older individuals than in younger individuals. Compared with individuals of healthy weight (BMI 18·5-24·9 kg/m2), life expectancy from age 40 years was 4·2 years shorter in obese (BMI ≥30·0 kg/m2) men and 3·5 years shorter in obese women, and 4·3 years shorter in underweight (BMI <18·5 kg/m2) men and 4·5 years shorter in underweight women. When smokers were included in analyses, results for most causes of death were broadly similar, although marginally stronger associations were seen among people with lower BMI, suggesting slight residual confounding by smoking. INTERPRETATION: BMI had J-shaped associations with overall mortality and most specific causes of death; for mental and behavioural, neurological, and external causes, lower BMI was associated with increased mortality risk. FUNDING: Wellcome Trust.

Long-term effects of bariatric surgery on acute kidney injury: a propensity-matched cohort in the UK Clinical Practice Research Datalink.

OBJECTIVE: Bariatric surgery is an effective method of weight reduction and has been associated with acute kidney injury (AKI) as a perioperative event. However, the long-term effects of the weight reduction after surgery on AKI are unknown. The objective of this study is to quantify the association of bariatric surgery with later risk of AKI. DESIGN: This study uses a propensity score-matched cohort of patients from the UK Clinical Practice Research Datalink database with and without bariatric surgery to compare rates of AKI episodes derived from linkage to the Hospital Episode Statistics. SETTING: England, UK. PARTICIPANTS: We included 2643 patients with bariatric surgery and 2595 patients without. RESULTS: Results were compatible with an increased risk of AKI in the first 30 days following surgery compared with patients without surgery, but AKI incidence was substantially decreased in patients with bariatric surgery during long-term follow-up (rate ratio 0.37, 95% CI 0.23 to 0.61) even after accounting for chronic kidney disease status at baseline. Over the whole period of follow-up, bariatric surgery had a net protective effect on risk of AKI (rate ratio 0.45, 95% CI 0.28 to 0.72). CONCLUSIONS: Bariatric surgery was associated with protective effects on AKI incidence during long-term follow-up. While the risk of AKI may be increased within the first 30 days, the net effect seen was beneficial.

Exacerbation risk and characterisation of the UK's asthma population from infants to old age.

BACKGROUND: Few studies have examined the characteristics of a general asthma population; most have focused on more severe patients or severe exacerbations. METHODS: This population-based cohort study, from April 2007 to September 2015, used linked primary and secondary care electronic healthcare records (Clinical Practice Research Datalink, Hospital Episode Statistics). Characteristics of four age cohorts, 'Under 5s', '5 to 17s', '18 to 54s', '55+', were described. Exacerbation risk factors, including asthma severity (measured by the British Thoracic Society (BTS) stepwise approach), were assessed using Poisson regression. RESULTS: 424 326 patients with current asthma were eligible (n, median follow-up: 'Under 5s'=17 320, 1 year; '5 to 17s'=82 707, 3.3 years; '18 to 54s'=210 724, 4 years; '55+'=113 575, 5.1 years). Over 60% of the total study population had mild asthma (BTS steps 1/2). There were differences between the cohort's characteristics, including by gender, disease severity and exacerbation pattern. The rate of exacerbations was highest in the oldest cohort and lowest in the '5 to 17s' cohort (rate per 10 person-years (95% CI), 'Under 5s'=4.27 (4.18 to 4.38), '5 to 17s'=1.48 (1.47 to 1.50), '18 to 54s'=3.22 (3.21 to 3.24), '55+'=9.40 (9.37 to 9.42)). In all cohorts, exacerbation rates increased with increasing asthma severity, after adjusting for confounders including gender, socioeconomic status, smoking, body mass index, atopy, rhinitis, gastro-oesophageal reflux, anxiety, depression and COPD. CONCLUSION: The majority of UK patients with asthma had mild asthma and did not experience an exacerbation during follow-up. Patients aged ≥55 years had the lowest proportion with mild asthma and highest rate of exacerbations; the opposite was found in patients aged between 5 and 18 years.

Phosphodiesterase Type 5 Inhibitors and Risk of Malignant Melanoma: Matched Cohort Study Using Primary Care Data from the UK Clinical Practice Research Datalink.

BACKGROUND: Laboratory evidence suggests that reduced phosphodiesterase type 5 (PDE5) expression increases the invasiveness of melanoma cells; hence, pharmacological inhibition of PDE5 could affect melanoma risk. Two major epidemiological studies have investigated this and come to differing conclusions. We therefore aimed to investigate whether PDE5 inhibitor use is associated with an increased risk of malignant melanoma, and whether any increase in risk is likely to represent a causal relationship. METHODS AND FINDINGS: We conducted a matched cohort study using primary care data from the UK Clinical Practice Research Datalink. All men initiating a PDE5 inhibitor and with no prior cancer diagnosis were identified and matched on age, diabetes status, and general practice to up to four unexposed controls. Ever use of a PDE5 inhibitor and time-updated cumulative number of PDE5 inhibitor prescriptions were investigated as exposures, and the primary outcome was malignant melanoma. Basal cell carcinoma, solar keratosis, and colorectal cancer were investigated as negative control outcomes to exclude bias. Hazard ratios (HRs) were estimated from Cox models stratified by matched set and adjusted for potential confounders. 145,104 men with ≥1 PDE5 inhibitor prescription, and 560,933 unexposed matched controls were included. In total, 1,315 incident malignant melanoma diagnoses were observed during 3.44 million person-years of follow-up (mean 4.9 y per person). After adjusting for potential confounders, there was weak evidence of a small positive association between PDE5 inhibitor use and melanoma risk (HR = 1.14, 95% CI 1.01-1.29, p = 0.04). A similar increase in risk was seen for the two negative control outcomes related to sun exposure (HR = 1.15, 95% CI 1.11-1.19, p < 0.001, for basal cell carcinoma; HR = 1.21, 95% CI 1.17-1.25, p < 0.001, for solar keratosis), but there was no increased risk for colorectal cancer (HR = 0.91, 95% CI 0.85-0.98, p = 0.01). There was no evidence that risk increased with number of prescriptions received (p-trend = 0.83). In a post hoc analysis, there was strong evidence that solar keratosis was associated with future PDE5 inhibitor use (odds ratio = 1.28, 95% CI 1.23-1.34, p < 0.001), suggesting that men with higher sun exposure were more likely to become PDE5 inhibitor users. However, a limitation of our study was that we did not have individual-level data on sun exposure, so we could not directly control for this in the primary analysis. CONCLUSIONS: Our results were not consistent with PDE5 inhibitors being causally associated with melanoma risk, and strongly suggest that observed risk increases are driven by greater sun exposure among patients exposed to a PDE5 inhibitor.

Bariatric Surgery in the United Kingdom: A Cohort Study of Weight Loss and Clinical Outcomes in Routine Clinical Care.

BACKGROUND: Bariatric surgery is becoming a more widespread treatment for obesity. Comprehensive evidence of the long-term effects of contemporary surgery on a broad range of clinical outcomes in large populations treated in routine clinical practice is lacking. The objective of this study was to measure the association between bariatric surgery, weight, body mass index, and obesity-related co-morbidities. METHODS AND FINDINGS: This was an observational retrospective cohort study using data from the United Kingdom Clinical Practice Research Datalink. All 3,882 patients registered in the database and with bariatric surgery on or before 31 December 2014 were included and matched by propensity score to 3,882 obese patients without surgery. The main outcome measures were change in weight and body mass index over 4 y; incident diagnoses of type 2 diabetes mellitus (T2DM), hypertension, angina, myocardial infarction (MI), stroke, fractures, obstructive sleep apnoea, and cancer; mortality; and resolution of hypertension and T2DM. Weight measures were available for 3,847 patients between 1 and 4 mo, 2,884 patients between 5 and 12 mo, and 2,258 patients between 13 and 48 mo post-procedure. Bariatric surgery patients exhibited rapid weight loss for the first four postoperative months, at a rate of 4.98 kg/mo (95% CI 4.88-5.08). Slower weight loss was sustained to the end of 4 y. Gastric bypass (6.56 kg/mo) and sleeve gastrectomy (6.29 kg/mo) were associated with greater initial weight reduction than gastric banding (2.77 kg/mo). Protective hazard ratios (HRs) were detected for bariatric surgery for incident T2DM, 0.68 (95% CI 0.55-0.83); hypertension, 0.35 (95% CI 0.27-0.45); angina, 0.59 (95% CI 0.40-0.87);MI, 0.28 (95% CI 0.10-0.74); and obstructive sleep apnoea, 0.55 (95% CI 0.40-0.87). Strong associations were found between bariatric surgery and the resolution of T2DM, with a HR of 9.29 (95% CI 6.84-12.62), and between bariatric surgery and the resolution of hypertension, with a HR of 5.64 (95% CI 2.65-11.99). No association was detected between bariatric surgery and fractures, cancer, or stroke. Effect estimates for mortality found no protective association with bariatric surgery overall, with a HR of 0.97 (95% CI 0.66-1.43). The data used were recorded for the management of patients in primary care and may be subject to inaccuracy, which would tend to lead to underestimates of true relative effect sizes. CONCLUSIONS: Bariatric surgery as delivered in the UK healthcare system is associated with dramatic weight loss, sustained at least 4 y after surgery. This weight loss is accompanied by substantial improvements in pre-existing T2DM and hypertension, as well as a reduced risk of incident T2DM, hypertension, angina, MI, and obstructive sleep apnoea. Widening the availability of bariatric surgery could lead to substantial health benefits for many people who are morbidly obese.

Angiotensin receptor blockers and risk of dementia: cohort study in UK Clinical Practice Research Datalink.

AIMS: This was a cohort study to evaluate whether individuals exposed to angiotensin receptor blockers have a reduced risk of dementia compared with those exposed to angiotensin-converting enzyme inhibitors. METHODS: The study included new users of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (from 1995 to 2010) from UK primary care practices contributing to the Clinical Research Practice Datalink. The association between exposure to angiotensin receptor blockers and the risk of incident dementia was analysed using a Cox model, adjusting for age, sex, body mass index, diabetes, hypertension, heart failure, statin use, socioeconomic status, alcohol, smoking, number of consultations and calendar year. RESULTS: A total of 426 089 persons were included in the primary analysis, with 45 541 persons exposed to angiotensin receptor blockers and the remainder to angiotensin-converting enzyme inhibitors. The total number of new diagnoses of dementia was 6517. There was weak evidence of a decreased risk of dementia with exposure to angiotensin receptor blockers, with follow-up beginning at 1 year after the start of treatment (adjusted hazard ratio 0.92, 95% confidence interval 0.85-1.00). An analysis restricted to the first 12 months after the index date showed a larger effect on dementia risk (adjusted hazard ratio 0.60, 95% confidence interval 0.50-0.72). CONCLUSIONS: A small reduction in dementia risk was seen with angiotensin receptor blockers in comparison to angiotensin-converting enzyme inhibitors. However, the strongest association was seen in early follow-up, suggesting that the inverse association is unlikely to be causal, but instead reflects other important but unmeasured differences between angiotensin receptor blocker and angiotensin-converting enzyme inhibitor users.

A case-control study of drug risk factors for age-related macular degeneration.

OBJECTIVE: To investigate the association between age-related macular degeneration (AMD) and exposure to antacids, antithyroids, thyroid hormones, and thiazide diuretics. DESIGN: Matched case-control study. PARTICIPANTS: Population-based participants were selected from the United Kingdom General Practice Research Database. A total of 18,007 people with diagnosed AMD were compared with 86 169 controls matched for age, gender, and general practice. METHODS: Conditional logistic regression was used to determine the association between exposure to each drug group of interest and a diagnosis of AMD, adjusting for relevant confounding variables. MAIN OUTCOME MEASURES: The primary outcome was the odds ratio for the association between exposure to antacids, antithyroids, thyroid hormones, or thiazide diuretics and AMD. Secondary analyses were conducted to assess the effect of recent exposure to the drugs of interest, the total number of prescriptions received, and restricting the data set to participants with more than 2 years of observation time. RESULTS: The crude odds ratios for association between any record of drug exposure and AMD were as follows: 1.34 (95% confidence interval [CI], 1.29-1.39) for antacids; 1.15 (95% CI, 0.92-1.44) for antithyroids; 1.34 (95% CI, 1.29-1.39) for thyroid hormones; and 1.13 (95% CI, 1.08-1.17) for thiazide diuretics. After adjusting for consultation rate, observation time, diabetes, heart failure, hyperlipidemia, cardiovascular drug use, atherosclerosis, hypertension, aspirin use, hormone replacement therapy use, body mass index, alcohol consumption, and smoking, the odds ratios reduced to: 1.06 (95% CI, 1.02-1.10) for antacids, 0.98 (95% CI, 0.78-1.24) for antithyroids, 0.99 (95% CI, 0.92-1.06) for thyroid hormones, and 0.98 (95% CI, 0.94-1.02) for thiazides. Secondary analyses were consistent with these findings for all 4 drug categories. CONCLUSIONS: No association was detected between short- and medium-term use of antithyroids, thyroid hormones, and thiazide diuretics and the risk of AMD. Short- and medium-term use of antacids seems to be associated with a small increase in the risk of this disease. However, this increased risk is likely the result of residual confounding by smoking or uncontrolled confounding resulting from socioeconomic status. No conclusions could be drawn regarding longer-term use of each drug category.