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Summary COVID-19 has rapidly impacted on mortality worldwide.1 There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets. Working on behalf of NHS England we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major primary care electronic health records vendor. 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 1.59, 95%CI 1.53-1.65); older age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared to people with 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 risk factors for COVID-19 related death in the largest cohort study conducted by any country to date. OpenSAFELY is rapidly adding further patients’ records; we will update and extend results regularly.

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.

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.

BACKGROUND: On 8 December 2020 NHS England administered the first COVID-19 vaccination. AIM: To describe trends and variation in vaccine coverage in different clinical and demographic groups in the first 100 days of the vaccine rollout. DESIGN AND SETTING: With the approval of NHS England, a cohort study was conducted of 57.9 million patient records in general practice in England, in situ and within the infrastructure of the electronic health record software vendors EMIS and TPP using OpenSAFELY. METHOD: Vaccine coverage across various subgroups of Joint Committee on Vaccination and Immunisation (JCVI) priority cohorts is described. RESULTS: A total of 20 852 692 patients (36.0%) received a vaccine between 8 December 2020 and 17 March 2021. Of patients aged ≥80 years not in a care home (JCVI group 2) 94.7% received a vaccine, but with substantial variation by ethnicity (White 96.2%, Black 68.3%) and deprivation (least deprived 96.6%, most deprived 90.7%). Patients with pre-existing medical conditions were more likely to be vaccinated with two exceptions: severe mental illness (89.5%) and learning disability (91.4%). There were 275 205 vaccine recipients who were identified as care home residents (JCVI group 1; 91.2% coverage). By 17 March, 1 257 914 (6.0%) recipients had a second dose. CONCLUSION: The NHS rapidly delivered mass vaccination. In this study a data-monitoring framework was deployed using publicly auditable methods and a secure in situ processing model, using linked but pseudonymised patient-level NHS data for 57.9 million patients. Targeted activity may be needed to address lower vaccination coverage observed among certain key groups.

BACKGROUND: Long COVID describes new or persistent symptoms at least 4 weeks after onset of acute COVID-19. Clinical codes to describe this phenomenon were recently created. AIM: To describe the use of long-COVID codes, and variation of use by general practice, demographic variables, and over time. DESIGN AND SETTING: Population-based cohort study in English primary care. METHOD: Working on behalf of NHS England, OpenSAFELY data were used encompassing 96% of the English population between 1 February 2020 and 25 May 2021. The proportion of people with a recorded code for long COVID was measured overall and by demographic factors, electronic health record software system (EMIS or TPP), and week. RESULTS: Long COVID was recorded for 23 273 people. Coding was unevenly distributed among practices, with 26.7% of practices having never used the codes. Regional variation ranged between 20.3 per 100 000 people for East of England (95% confidence interval [CI] = 19.3 to 21.4) and 55.6 per 100 000 people in London (95% CI = 54.1 to 57.1). Coding was higher among females (52.1, 95% CI = 51.3 to 52.9) than males (28.1, 95% CI = 27.5 to 28.7), and higher among practices using EMIS (53.7, 95% CI = 52.9 to 54.4) than those using TPP (20.9, 95% CI = 20.3 to 21.4). CONCLUSION: Current recording of long COVID in primary care is very low, and variable between practices. This may reflect patients not presenting; clinicians and patients holding different diagnostic thresholds; or challenges with the design and communication of diagnostic codes. Increased awareness of diagnostic codes is recommended to facilitate research and planning of services, and also surveys with qualitative work to better evaluate clinicians' understanding of the diagnosis.

BackgroundPatients with COVID-19 are thought to be at higher risk of cardiometabolic and pulmonary complications, but quantification of that risk is limited. We aimed to describe the overall burden of these complications in survivors of severe COVID-19.MethodsWorking on behalf of NHS England, we used linked primary care records, death certificate and hospital data from the OpenSAFELY platform. We constructed three cohorts: patients discharged following hospitalisation with COVID-19, patients discharged following hospitalisation with pneumonia in 2019, and a frequency-matched cohort from the general population in 2019. We studied eight cardiometabolic and pulmonary outcomes. Absolute rates were measured in each cohort and Cox regression models were fitted to estimate age/sex adjusted hazard ratios comparing outcome rates between discharged COVID-19 patients and the two comparator cohorts.ResultsAmongst the population of 31,716 patients discharged following hospitalisation with COVID-19, rates for majority of outcomes peaked in the first month post-discharge, then declined over the following four months. Patients in the COVID-19 population had markedly increased risk of all outcomes compared to matched controls from the 2019 general population, especially for pulmonary embolism (HR 12.86; 95% CI: 11.23 - 14.74). Outcome rates were more similar when comparing patients discharged with COVID-19 to those discharged with pneumonia in 2019, although COVID-19 patients had increased risk of type 2 diabetes (HR 1.23; 95% CI: 1.05 - 1.44).InterpretationCardiometabolic and pulmonary adverse outcomes are markedly raised following hospitalisation for COVID-19 compared to the general population. However, the excess risks were more comparable to those seen following hospitalisation with pneumonia. Identifying patients at particularly high risk of outcomes would inform targeted preventive measures.FundingWellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, UK Research and Innovation, Health and Safety Executive.

BackgroundClose contact with children may provide cross-reactive immunity to SARs-CoV-2 due to more frequent prior coryzal infections from seasonal coronaviruses. Alternatively, close contact with children may increase risk of SARs-CoV-2 infection. We investigated whether risk of infection with SARs-CoV-2 and severe outcomes differed between adults living with and without children.MethodsWorking on behalf of NHS England, we conducted a population-based cohort study using primary care data and pseudonymously-linked hospital and intensive care admissions, and death records, from patients registered in general practices representing 40% of England. Using multivariable Cox regression, we calculated fully-adjusted hazard ratios (HR) of outcomes from 1st February-3rd August 2020 comparing adults living with and without children in the household.FindingsAmong 9,157,814 adults ≤65 years, living with children 0-11 years was not associated with increased risks of recorded SARS-CoV-2 infection, COVID-19 related hospital or ICU admission but was associated with reduced risk of COVID-19 death (HR 0.75, 95%CI 0.62-0.92). Living with children aged 12-18 years was associated with a small increased risk of recorded SARS-CoV-2 infection (HR 1.08, 95%CI 1.03-1.13), but not associated with other COVID-19 outcomes. Living with children of any age was also associated with lower risk of dying from non-COVID-19 causes. Among 2,567,671 adults >65 years there was no association between living with children and outcomes related to SARS-CoV-2. We observed no consistent changes in risk following school closure.InterpretationFor adults living with children there is no evidence of an increased risk of severe COVID-19 outcomes. These findings have implications for determining the benefit-harm balance of children attending school in the COVID-19 pandemic.FundingThis work was supported by the Medical Research Council MR/V015737/1.Research in contextEvidence before this studyWe searched MEDLINE on 19th October 2020 for population-based epidemiological studies comparing the risk of SARS-CoV-2 infection and COVID-19 disease in people living with and without children. We searched for articles published in 2020, with abstracts available, and terms “(children or parents or dependants) AND (COVID or SARS-CoV-2 or coronavirus) AND (rate or hazard or odds or risk), in the title, abstract or keywords. 244 papers were identified for screening but none were relevant. One additional study in preprint was identified on medRxiv and found a reduced risk of hospitalisation for COVID-19 and a positive SARS-CoV-2 infection among adult healthcare workers living with children.Added value of this studyThis is the first population-based study to investigate whether the risk of recorded SARS-CoV-2 infection and severe outcomes from COVID-19 differ between adults living in households with and without school-aged children during the UK pandemic. Our findings show that for adults living with children there is no evidence of an increased risk of severe COVID-19 outcomes although there may be a slightly increased risk of recorded SARS-CoV-2 infection for working-age adults living with children aged 12 to 18 years. Working-age adults living with children 0 to 11 years have a lower risk of death from COVID-19 compared to adults living without children, with the effect size being comparable to their lower risk of death from any cause. We observed no consistent changes in risk of recorded SARS-CoV-2 infection and severe outcomes from COVID-19 comparing periods before and after school closure.Implications of all the available evidenceOur results demonstrate no evidence of serious harms from COVID-19 to adults in close contact with children, compared to those living in households without children. This has implications for determining the benefit-harm balance of children attending school in the COVID-19 pandemic.

BACKGROUND: Early descriptions of patients admitted to hospital during the COVID-19 pandemic showed a lower prevalence of asthma and chronic obstructive pulmonary disease (COPD) than would be expected for an acute respiratory disease like COVID-19, leading to speculation that inhaled corticosteroids (ICSs) might protect against infection with severe acute respiratory syndrome coronavirus 2 or the development of serious sequelae. We assessed the association between ICS and COVID-19-related death among people with COPD or asthma using linked electronic health records (EHRs) in England, UK. METHODS: In this observational study, we analysed patient-level data for people with COPD or asthma from primary care EHRs linked with death data from the Office of National Statistics using the OpenSAFELY platform. The index date (start of follow-up) for both cohorts was March 1, 2020; follow-up lasted until May 6, 2020. For the COPD cohort, individuals were eligible if they were aged 35 years or older, had COPD, were a current or former smoker, and were prescribed an ICS or long-acting β agonist plus long-acting muscarinic antagonist (LABA-LAMA) as combination therapy within the 4 months before the index date. For the asthma cohort, individuals were eligible if they were aged 18 years or older, had been diagnosed with asthma within 3 years of the index date, and were prescribed an ICS or short-acting β agonist (SABA) only within the 4 months before the index date. We compared the outcome of COVID-19-related death between people prescribed an ICS and those prescribed alternative respiratory medications: ICSs versus LABA-LAMA for the COPD cohort, and low-dose or medium-dose and high-dose ICSs versus SABAs only in the asthma cohort. We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs for the association between exposure categories and the outcome in each population, adjusted for age, sex, and all other prespecified covariates. We calculated e-values to quantify the effect of unmeasured confounding on our results. FINDINGS: We identified 148 557 people with COPD and 818 490 people with asthma who were given relevant respiratory medications in the 4 months before the index date. People with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA-LAMA combinations (adjusted HR 1·39 [95% CI 1·10-1·76]). Compared with those prescribed SABAs only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1·55 [1·10-2·18]), whereas those given a low or medium dose were not (1·14 [0·85-1·54]). Sensitivity analyses showed that the apparent harmful association we observed could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS that were not recorded in the database (e value lower 95% CI 1·43). INTERPRETATION: Our results do not support a major role for regular ICS use in protecting against COVID-19-related death among people with asthma or COPD. Observed increased risks of COVID-19-related death can be plausibly explained by unmeasured confounding due to disease severity. FUNDING: UK Medical Research Council.

BackgroundConcerns have been raised that the response to the UK COVID-19 pandemic may have worsened physical and mental health, and reduced use of health services. However, the scale of the problem is unquantified, impeding development of effective mitigations. We asked what has happened to general practice contacts for acute physical and mental health outcomes during the pandemic?MethodsUsing electronic health records from the Clinical Research Practice Datalink (CPRD) Aurum (2017-2020), we calculated weekly primary care contacts for selected acute physical and mental health conditions (including: anxiety, depression, acute alcohol-related events, asthma and chronic obstructive pulmonary disease [COPD] exacerbations, cardiovascular and diabetic emergencies). We used interrupted time series (ITS) analysis to formally quantify changes in conditions after the introduction of population-wide restrictions (‘lockdown’) compared to the period prior to their introduction in March 2020.FindingsThe overall population included 9,863,903 individuals on 1st January 2017. Primary care contacts for all conditions dropped dramatically after introduction of population-wide restrictions. By July 2020, except for unstable angina and acute alcohol-related events, contacts for all conditions had not recovered to pre-lockdown levels. The largest reductions were for contacts for: diabetic emergencies (OR: 0.35, 95% CI: 0.25-0.50), depression (OR: 0.53, 95% CI: 0.52-0.53), and self-harm (OR: 0.56, 95% CI: 0.54-0.58).InterpretationThere were substantial reductions in primary care contacts for acute physical and mental conditions with restrictions, with limited recovery by July 2020. It is likely that much of the deficit in care represents unmet need, with implications for subsequent morbidity and premature mortality. The conditions we studied are sufficiently severe that any unmet need will have substantial ramifications for the people experiencing the conditions and healthcare provision. Maintaining access must be a key priority in future public health planning (including further restrictions).FundingWellcome Trust Senior Fellowship (SML), Health Data Research UK.RESULTS IN CONTEXTEvidence before this studyA small study in 47 GP practices in a largely deprived, urban area of the UK (Salford) reported that primary care consultations for four broad diagnostic groups (circulatory disease, common mental health problems, type 2 diabetes mellitus and malignant cancer) declined by 16-50% between March and May 2020, compared to what was expected based on data from January 2010 to March 2020. We searched Medline for other relevant evidence of the indirect effect of the COVID-19 pandemic on physical and mental health from inception to September 25th 2020, for articles published in English, with titles including the search terms (“covid*” or “coronavirus” or “sars-cov-2”), and title or abstracts including the search terms (“indirect impact” or “missed diagnos*” or “missing diagnos*” or “delayed diagnos*” or ((“present*” or “consult*” or “engag*” or “access*”) AND (“reduction” or “decrease” or “decline”)). We found no further studies investigating the change in primary care contacts for specific physical- and mental-health conditions indirectly resulting from the COVID-19 pandemic or its control measures. There has been a reduction in hospital admissions and presentations to accident and emergency departments in the UK, particularly for myocardial infarctions and cerebrovascular accidents. However, there is no published evidence specifically investigating the changes in primary care contacts for severe acute physical and mental health conditions.Added value of this studyTo our knowledge this is the first study to explore changes in healthcare contacts for acute physical and mental health conditions in a large population representative of the UK. We used electronic primary care health records of nearly 10 million individuals across the UK to investigate the indirect impact of COVID-19 on primary care contacts for mental health, acute alcohol-related events, asthma/chronic obstructive pulmonary disease (COPD) exacerbations, and cardiovascular and diabetic emergencies up to July 2020. For all conditions studied, we found primary care contacts dropped dramatically following the introduction of population-wide restriction measures in March 2020. By July 2020, with the exception of unstable angina and acute alcohol-related events, primary care contacts for all conditions studied had not recovered to pre-lockdown levels. In the general population, estimates of the absolute reduction in the number of primary care contacts up to July 2020, compared to what we would expect from previous years varied from fewer than 10 contacts per million for some cardiovascular outcomes, to 12,800 per million for depression and 6,600 for anxiety. In people with COPD, we estimated there were 43,900 per million fewer contacts for COPD exacerbations up to July 2020 than what we would expect from previous years.Implicatins of all the available evidenceWhile our results may represent some genuine reduction in disease frequency (e.g. the restriction measures may have improved diabetic glycaemic control due to more regular daily routines at home), it is more likely the reduced primary care conatcts we saw represent a substantial burden of unmet need (particularly for mental health conditions) that may be reflected in subsequent increased mortality and morbidity. Health service providers should take steps to prepare for increased demand in the coming months and years due to the short and longterm ramifications of reduced access to care for severe acute physical and mental health conditions. Maintaining access to primary care is key to future public health planning in relation to the pandemic.

BACKGROUND: Haloperidol remains a frequently prescribed first-generation antipsychotic. However, haloperidol-associated mortality risk by all causes, cardiovascular disease (CVD), and pneumonia compared with other antipsychotics is unknown. OBJECTIVE: This study investigated the mortality risk associated with long-term haloperidol treatment versus that with other antipsychotics. METHODS: We identified incident antipsychotic users from 2004 to 2014 in the Clinical Data Analysis and Reporting System (CDARS), a population-based clinical database managed by the Hong Kong Hospital Authority. We included patients who were aged ≥ 18 and received antipsychotics for any indication apart from terminal illnesses or management of acute behavioural disturbance. Patients on haloperidol and other antipsychotic agents (risperidone, quetiapine, olanzapine, chlorpromazine, aripiprazole, sulpiride, amisulpride, or trifluoperazine) were matched by propensity score. Hazard ratios (HRs) for all-cause mortality and death due to CVD and pneumonia were estimated with 95% confidence intervals (CIs) using a Cox proportional hazards model. RESULTS: In total, 136,593 users of antipsychotics were included. During a mean follow-up of 3.2 years, the incidence of all-cause mortality ranged from 186.8/1000 person-years for haloperidol to 10.4/1000 person-years for trifluoperazine. The risk of all-cause mortality was lower with non-haloperidol antipsychotics than with haloperidol, with HRs ranging from 0.68 (95% CI 0.64-0.72 [chlorpromazine]) to 0.43 (95% CI 0.36-0.53 [trifluoperazine]). Risperidone, quetiapine, sulpiride, chlorpromazine, aripiprazole, and trifluoperazine were associated with a significantly lower risk of pneumonia-related mortality. A significantly lower risk of CVD mortality was observed for risperidone, sulpiride, chlorpromazine, and quetiapine. CONCLUSION: Haloperidol was associated with increased overall mortality when compared with other antipsychotics in long-term follow-up. Treatment with haloperidol should be carefully considered, especially in older patients and patients at risk of CVD or pneumonia, since the risk of death appears to be lower with non-haloperidol agents.

BACKGROUND: Individuals may still develop gastric cancer even after Helicobacter pylori eradication. We aimed to investigate statin effect on gastric cancer development in H. pylori-eradicated subjects. METHODS: All adult subjects who were prescribed clarithromycin-based triple therapy between 2003 and 2012 were identified in this retrospective cohort study utilizing a territory-wide electronic healthcare database. Patients were observed from index date of H. pylori therapy, and censored at gastric cancer diagnosis, death, or December 2015 (study end date). Statin use was defined as ≥180-day use after index date. Exclusion criteria included gastric cancer diagnosed within the first year after index date, previous gastric cancer or gastrectomy, and H. pylori treatment failure. Subdistribution hazard ratio (SHR) of gastric cancer with statins was calculated by competing risk regression with propensity score (PS) analysis matching 19 variables (age, sex, comorbidities, and other drug usage, including proton pump inhibitors, nonsteroidal anti-inflammatory drugs, aspirin, cyclooxygenase-2 inhibitors, and metformin). RESULTS: During a median follow-up of 7.6 years (interquartile range = 5.1-10.3), 169 (0.27%) of 63,605 patients developed gastric cancer at an incidence rate of 3.5 per 10,000 person-years. Among 22,870 PS-matched subjects, statins were associated with a lower gastric cancer risk (SHR = 0.34; 95% confidence interval, 0.19-0.61), in a duration- and dose-response manner (P trend < 0.05). CONCLUSIONS: Statins were associated with a lower gastric cancer risk in a duration- and dose-response manner among H. pylori-eradicated patients. IMPACT: This study provides evidence on the additional benefits of statins as chemopreventive agents against gastric cancer among H. pylori-eradicated patients.

BACKGROUND: Although prior studies showed metformin could reduce gastric cancer (GC) risk in patients with diabetes mellitus, they failed to adjust for Helicobacter pylori infection and glycemic control. We aimed to investigate whether metformin reduced GC risk in H. pylori-eradicated diabetic patients and its association with glycemic control. METHODS: This was a territory-wide cohort study using hospital registry database, recruiting all diabetic patients who were prescribed clarithromycin-based triple therapy for H. pylori infection from 2003 to 2012. Subjects were observed from H. pylori therapy prescription until GC diagnosis, death, or end of study (December 2015). Exclusion criteria included GC diagnosed within first year of H. pylori therapy, prior history of GC or gastrectomy, and failure of H. pylori eradication. The hazard ratio (HR) of GC with metformin (defined as at least 180-day use) was estimated by Cox model with propensity score adjustment for covariates (age, sex, comorbidities, medications [including insulin], and time-weighted average hemoglobin A1c [HbA1c]). All statistical tests were two-sided. RESULTS: During a median follow-up of 7.1 years (IQR = 4.7-9.8), 37 (0.51%) of 7266 diabetic patients developed GC at a median age of 76.4 years (IQR = 64.8-81.5 years). Metformin use was associated with a reduced GC risk (adjusted HR = 0.49, 95% CI = 0.24 to 0.98). There was a trend towards a lower GC risk with increasing duration (Ptrend = .01) and dose of metformin (Ptrend = .02). HbA1c level was not an independent risk factor for GC. CONCLUSIONS: Metformin use was associated with a lower GC risk among H. pylori-eradicated diabetic patients in a duration- and dose-response manner, which was independent of HbA1c level.

To the Editor: We are thankful to Prof. Nguyen and Dr. Tran for their interest in our study and we appreciate the opportunity to respond to their comments. As Prof. Nguyen and Dr. Tran suggested that censoring patients at the time of switching medications might have inflated the effect size, we investigated this potential bias by excluding patients with switching of medications. Of the 3,081 alendronate-treated patients, 281 patients (9.1%) switched the therapy during the study period. After excluding these patients, we observed similar findings (Table), suggesting that bias due to treatment of censoring data should be minimal in our study.

BACKGROUND:Haloperidol remains a frequently prescribed first-generation antipsychotic. However, haloperidol-associated mortality risk by all causes, cardiovascular disease (CVD), and pneumonia compared with other antipsychotics is unknown. OBJECTIVE:This study investigated the mortality risk associated with long-term haloperidol treatment versus that with other antipsychotics. METHODS:We identified incident antipsychotic users from 2004 to 2014 in the Clinical Data Analysis and Reporting System (CDARS), a population-based clinical database managed by the Hong Kong Hospital Authority. We included patients who were aged ≥ 18 and received antipsychotics for any indication apart from terminal illnesses or management of acute behavioural disturbance. Patients on haloperidol and other antipsychotic agents (risperidone, quetiapine, olanzapine, chlorpromazine, aripiprazole, sulpiride, amisulpride, or trifluoperazine) were matched by propensity score. Hazard ratios (HRs) for all-cause mortality and death due to CVD and pneumonia were estimated with 95% confidence intervals (CIs) using a Cox proportional hazards model. RESULTS:In total, 136,593 users of antipsychotics were included. During a mean follow-up of 3.2 years, the incidence of all-cause mortality ranged from 186.8/1000 person-years for haloperidol to 10.4/1000 person-years for trifluoperazine. The risk of all-cause mortality was lower with non-haloperidol antipsychotics than with haloperidol, with HRs ranging from 0.68 (95% CI 0.64-0.72 [chlorpromazine]) to 0.43 (95% CI 0.36-0.53 [trifluoperazine]). Risperidone, quetiapine, sulpiride, chlorpromazine, aripiprazole, and trifluoperazine were associated with a significantly lower risk of pneumonia-related mortality. A significantly lower risk of CVD mortality was observed for risperidone, sulpiride, chlorpromazine, and quetiapine. CONCLUSION:Haloperidol was associated with increased overall mortality when compared with other antipsychotics in long-term follow-up. Treatment with haloperidol should be carefully considered, especially in older patients and patients at risk of CVD or pneumonia, since the risk of death appears to be lower with non-haloperidol agents.

The risk of cardiovascular events (CVEs) with alendronate use in real-world hip fracture patients is unknown. This study aimed to investigate the risk of CVE with and without use of alendronate in patients with hip fracture. We conducted a retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with hip fracture from 2005 through 2013 were followed until November 6, 2016. Alendronate and other antiosteoporosis medications use during the study period were examined. We matched treated and nontreated patients based on time-dependent propensity score. The risks of cardiovascular mortality, myocardial infarction, and stroke between treatment groups were evaluated using conditional Cox regression stratified by match pairs. To examine the associations over time, outcomes were assessed at 1 year, 3 years, 5 years, and 10 years. Among 34,991 patients with newly diagnosed hip fracture, 4602 (13.2%) received antiosteoporosis treatment during follow-up. Physical functioning or survival prospect was not significantly different between treated and nontreated patients. A total of 4594 treated patients were matched with 13,568 nontreated patients. Results of Cox regression analysis revealed that alendronate was associated with a significantly lower risk of 1-year cardiovascular mortality (HR 0.33; 95% CI, 0.17 to 0.65) and incident myocardial infarction (HR 0.55; 95% CI, 0.34 to 0.89), whereas marginally significant reduction in risk of stroke was observed at 5 years and 10 years (HR at 5 years: 0.82; 95% CI, 0.67 to 1.00; p = 0.049; HR at 10 years: 0.83; 95% CI, 0.69 to 1.01; p = 0.065). The strength of the association declined over time but remained significant. Similar results were observed when all nitrogen-containing bisphosphonates (N-BPs) were analyzed together. These findings were robust in multiple sensitivity analyses. Additional studies in other population samples and randomized clinical trials may be warranted to further understand the relationship between use of various antiosteoporosis medication and risk of CVE in patients with hip fracture. © 2018 American Society for Bone and Mineral Research.

BACKGROUND & AIMS: Although eradication of Helicobacter pylori infection reduces the risk of gastric cancer, few data are available on its effects in older subjects. We compared the age-specific risk of gastric cancer in a large cohort of subjects who received H pylori eradication therapy vs a matched general population. METHODS: We searched the Hospital Authority database of Hong Kong to identify individuals with H pylori infection who had received a course of clarithromycin-containing eradication therapy from January 2003 through December 2012. We compared the gastric cancer incidence in this cohort with the expected incidence for the local general population by retrieving the gastric cancer incidence of the age- and sex-matched population from 2003 through 2014 (the latest available year) from the Hong Kong Cancer Registry. The primary outcome was the incidence of gastric cancer development in the cohort treated for H pylori infection vs the expected number of gastric cancer cases in the general population. Analyses were conducted by a priori age groups of less than 40 years, 40-59 years, and 60 years or older. RESULTS: Among 73,237 subjects infected with H pylori who received eradication therapy, 200 (0.27%) developed gastric cancer during a median follow-up time of 7.6 years. Compared with the matched general population, the gastric cancer risk was significantly lower in subjects 60 years or older who had received H pylori treatment (standardized incidence ratio [SIR], 0.82; 95% confidence interval [CI], 0.69-0.97; P = .02) but not in younger groups. When data were stratified based on time from H pylori treatment (less than 5 years, 5-9 years, and 10 or more years), the risk of gastric cancer was significantly lower than the general population 10 or more years after eradication in the group 40-59 years old (SIR 0.32; 95% CI, 0.08-0.88; P = .04) and the group 60 years or older (SIR, 0.42; 95% CI, 0.42-0.84; P = .02) than the other age groups. CONCLUSIONS: In an analysis of data from a public hospital database on Hong Kong, we associated treatment of H pylori infection with a lower risk of gastric cancer, particularly in older subjects, 10 or more years after treatment.

INTRODUCTION: Leukotriene-modifying agents (LTMAs) including montelukast, zafirlukast, and zileuton are approved by the US Food and Drug Administration (FDA) for the treatment of asthma and allergic rhinitis. Various neuropsychiatric events (NEs) have been reported; however, the evidence of the association is conflicting. This systematic review investigates the association between NEs and LTMAs by assessing the relevant published literature. METHODS: PubMed, EMBASE, MEDLINE, and Cochrane Library were searched using keywords. Studies designed to investigate the association were eligible for inclusion without restriction to any study design or language. The primary outcome was defined as suicidal conditions, while secondary outcomes included all other NEs. RESULTS: Thirty-three studies were included for a narrative review. Four observational studies did not find a significant association, while ten pharmacovigilance studies using different global databases detected the signals. Notably, some studies suggest that the FDA warning issued in 2008 might have influenced the reporting rate of NEs as a result of increased awareness. LIMITATIONS: The risk of NEs was not quantified, because of the lack of randomized controlled trials and observational studies investigating the association. CONCLUSION: Many pharmacovigilance studies have been conducted to determine the association between NEs and LTMAs, but there is limited evidence from observational studies. High-quality epidemiological studies should be conducted to evaluate the association and quantify the risk, not only in children, but also in adults.

Background: Despite successful H. pylori (HP) eradication, some individuals remain at risk of developing gastric cancer (GC). Previous studies showed that aspirin was associated with a reduced GC risk. However, whether aspirin can reduce GC risk in HP-eradicated subjects remains unknown. We aimed to determine the chemopreventive effect of aspirin in HP-eradicated subjects. Methods: We identified subjects who had received a prescription of clarithromycin-based triple therapy for HP between 2003 and 2012 from a territory-wide health care database. The observation period started from commencement of HP therapy (index date), and the follow-up was censored at the end of the study (December 2015), death, or GC diagnosis. Aspirin use was defined as use once or more often weekly. Subjects who failed HP eradication or were diagnosed with GC within 12 months of HP therapy were excluded. The hazard ratio (HR) of GC with aspirin use was calculated by Cox model with Propensity Score adjustment for age, sex, comorbidities, and concurrent medications. All statistical tests were two-sided. Results: The median follow-up was 7.6 years (interquartile range [IQR] = 5.1-10.3 years), and 169 (0.27%) out of 63 605 patients developed GC. The incidence rate of GC was 3.5 per 10 000 person-years. Aspirin use was associated with a reduced GC risk (HR = 0.30, 95% confidence interval [CI] = 0.15 to 0.61). The risk of GC decreased with increasing frequency, duration, and dose of aspirin (all Ptrend < .001). Conclusions: Aspirin use was associated with a frequency-, dose-, and duration-dependent reduction in GC risk after HP eradication. The effect was most prominent in those who used aspirin daily or for five or more years.

INTRODUCTION: It was postulated that antibiotics including macrolides could be used for the secondary prevention of coronary heart disease but recent studies showed that macrolides increase the cardiovascular risk. We aimed to review the evidence of cardiovascular risk associated with macrolides regarding duration of effect and risk factors; and to explore the potential effect of statins for the prevention of cardiovascular events as a result of macrolide use. METHODS: Several electronic databases (PubMed, EMBASE, Cochrane library) were searched to identify eligible studies. Observational studies and randomized controlled trials that investigated the association between macrolides and cardiovascular events in adults aged ≥18 years were included. A meta-analysis was conducted to investigate the short- and long-term risks of cardiovascular mortality, myocardial infarction, arrhythmia, and stroke. Methodological quality was assessed by the Newcastle-Ottawa scale and the Cochrane Collaboration's tool. The body of evidence was evaluated by the Grading of Recommendations Assessment, Development, and Evaluation guidelines. RESULTS: Observational studies were found to have a short-term risk of cardiovascular outcomes including cardiovascular mortality, myocardial infarction, and arrhythmia associated with macrolides but no risk was found in randomized controlled trials. However, no association for long-term risk (ranging from >30 days to >3 years) was observed in observational studies or randomized controlled trials. LIMITATIONS: The included studies reported different units of denominators for absolute risk and used different outcome definitions, which might increase the heterogeneity. CONCLUSIONS: More studies are required to investigate the short-term cardiovascular outcomes associated with different types of macrolides. Future studies are warranted to evaluate the effect of statins for preventing excess acute cardiovascular events associated with clarithromycin or other macrolides.

IMPORTANCE: There is a concern that Helicobacter pylori therapy containing clarithromycin might be associated with acute neuropsychiatric events. OBJECTIVE: To examine the association between H pylori therapy containing clarithromycin and acute neuropsychiatric events. DESIGN, SETTING, AND PARTICIPANTS: A self-controlled case series study was conducted using the Clinical Data Analysis and Reporting System database in Hong Kong to explore any association. The exposure of interest was H pylori therapy containing clarithromycin in the outpatient setting. Study patients, 18 years or older at cohort entry, must have had both exposure to H pylori therapy containing clarithromycin and their first recorded neuropsychiatric events between January 1, 2003, and December 31, 2012. A post hoc nested case-control analysis was also performed in patients receiving H pylori therapy containing clarithromycin. MAIN OUTCOMES AND MEASURES: The primary outcome was composite neuropsychiatric events, while secondary outcomes were psychotic events and cognitive impairment. Risk periods in the self-controlled case series analysis were defined as 14-day preexposure period, current use (days 1-14 since prescription start date) and recent use (days 15-30). Age-adjusted incidence rate ratios (IRR) were estimated using the conditional Poisson regression. RESULTS: Of 66 559 patients who had at least 1 outpatient prescription of H pylori therapy containing clarithromycin. Their mean (SD) age at cohort entry was 50.8 (14.8 years); their mean age at first exposure was 55.4 (14.8) years, and 30 910 were male (46.4%). A total of 1824 patients had their first recorded composite neuropsychiatric events during the study period. An increased IRR of 4.12 (35 composite neuropsychiatric events during 72 person-years; 95% CI, 2.94-5.76) during current use was observed but not in recent use (9 events during 82 person-years; IRR, 0.95; 95% CI, 0.49-1.83) and 14-day preexposure period (14 events during 72 person-years; IRR, 1.63; 95% CI, 0.96-2.77) vs baseline (1766 events during 16 665 person-years). Similarly, both the risk of psychotic events and cognitive impairment increased during current use vs baseline, although this subsequently returned to baseline incidence levels during recent use. The crude absolute risks of composite neuropsychiatric events, psychotic events, and cognitive impairment during current use were 0.45, 0.12, and 0.12 per 1000 prescriptions, respectively. The nested case-control analysis also gave similar results to that of the self-controlled case series analysis. CONCLUSIONS AND RELEVANCE: This study shows evidence of a short-term increased risk of neuropsychiatric events associated with H pylori therapy containing clarithromycin.

There is significant variation in prescriptions among countries in clinical practice for the treatment of comorbidities associated with autism spectrum disorder (ASD). It has been suggested that many people with mental health disorders in low-/middle-income countries do not receive adequate treatment. Hence, this study investigated psychopharmacological treatment patterns for ASD comorbidities in 30 countries and the association between country's income and prescription rates. The IMS Prescribing Insights database was used to investigate prescription patterns for ASD comorbidity treatment from 2007 to 2012. Data were obtained from 30 countries in continents of Europe, Asia, Oceania, Central America, South America, and Africa. The gross domestic product (GDP) per capita was used as a proxy for each country's income. Spearman correlation was used to examine the association between prescription rate and GDP per capita. The highest prescription rates were found in Western Europe (3.89-36.36/10,000) while the lowest prescription rates were found in Asian countries, such as Turkey, Indonesia, Saudi Arabia, and Pakistan (0.04-0.82/10,000). The most commonly prescribed drug for ASD comorbidity treatment in most of the countries was risperidone, but antidepressants and antiepileptic drugs were also frequently prescribed. There was a significant positive correlation between GDP per capita and prescription rate (Spearman ρ = 0.60; P = 0.0011; 95% confidence interval 0.27-0.81), that is, the higher the GDP per capita, the higher the prescription rate. There are marked international differences in prescription rates, and this is partially accounted by economic factors. Future research should combine more data for ASD comorbidity treatment to explore the disparity of psychopharmacological treatment between countries.