Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.

BACKGROUND: Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease. METHODS: We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph. FINDINGS: Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (-0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. INTERPRETATION: We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted. FUNDING: Medical Research Council

The history of attention deficit hyperactivity disorder

The contemporary concept of attention deficit hyperactivity disorder (ADHD) as defined in the DSM-IV-TR (American Psychiatric Association 2000) is relatively new. Excessive hyperactive, inattentive, and impulsive children have been described in the literature since the nineteenth century. Some of the early depictions and etiological theories of hyperactivity were similar to current descriptions of ADHD. Detailed studies of the behavior of hyperactive children and increasing knowledge of brain function have changed the concepts of the fundamental behavioral and neuropathological deficits underlying the disorder. This article presents an overview of the conceptual history of modern-day ADHD

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

OpenSAFELY: impact of national guidance on switching anticoagulant therapy during COVID-19 pandemic.

BACKGROUND: Early in the COVID-19 pandemic, the National Health Service (NHS) recommended that appropriate patients anticoagulated with warfarin should be switched to direct-acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately coprescribed two anticoagulants following a medication change and associated monitoring. OBJECTIVE: To describe which people were switched from warfarin to DOACs; identify potentially unsafe coprescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic. METHODS: With the approval of NHS England, we conducted a cohort study using routine clinical data from 24 million NHS patients in England. RESULTS: 20 000 of 164 000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in coprescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. International normalised ratio (INR) testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420). CONCLUSIONS: Increased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people coprescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic

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

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

Inhaled corticosteroid use and risk COVID-19 related death among 966,461 patients with COPD or asthma: an OpenSAFELY analysis

AbstractBackgroundEarly descriptions of the coronavirus outbreak showed a lower prevalence of asthma and COPD than was expected for people diagnosed with COVID-19, leading to speculation that inhaled corticosteroids (ICS) may protect against infection with SARS-CoV-2, and development of serious sequelae. We evaluated the association between ICS and COVID-19 related death using linked electronic health records in the UK.MethodsWe conducted cohort studies on two groups of people (COPD and asthma) using the OpenSAFELY platform to analyse data from primary care practices linked to national death registrations. People receiving an ICS were compared to those receiving alternative respiratory medications. Our primary outcome was COVID-19 related death.FindingsWe identified 148,588 people with COPD and 817,973 people with asthma receiving relevant respiratory medications in the four months prior to 01 March 2020. People with COPD receiving ICS were at a greater risk of COVID-19 related death compared to those receiving a long-acting beta agonist (LABA) and a long-acting muscarinic antagonist (LAMA) (adjusted HR = 1.38, 95% CI = 1.08 – 1.75). People with asthma receiving high dose ICS were at an increased risk of death compared to those receiving a short-acting beta agonist (SABA) only (adjusted HR = 1.52, 95%CI = 1.08 – 2.14); the adjusted HR for those receiving low-medium dose ICS was 1.10 (95% CI = 0.82 – 1.49). Quantitative bias analyses indicated that an unmeasured confounder of only moderate strength of association with exposure and outcome could explain the observed associations in both populations.InterpretationThese results do not support a major role of ICS in protecting against COVID-19 related deaths. Observed increased risks of COVID-19 related death among people with COPD and asthma receiving ICS can be plausibly explained by unmeasured confounding due to disease severity.FundingThis work was supported by the Medical Research Council MR/V015737/1.</jats:sec

Hydroxychloroquine for prevention of COVID-19 mortality: a population-based cohort study

AbstractBackgroundHydroxychloroquine has been shown to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, but early clinical studies found no benefit treating patients with coronavirus disease 2019 (COVID-19). We set out to evaluate the effectiveness of hydroxychloroquine for prevention, as opposed to treatment, of COVID-19 mortality.MethodsWe pre-specified and conducted an observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, representing 40% of the general population in England. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use prior to the COVID-19 outbreak in England and risk of COVID-19 mortality among people with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Model adjustment was informed by a directed acyclic graph.ResultsOf 194,637 patients with RA or SLE, 30,569 (15.7%) received ≥ 2 prescriptions of hydroxychloroquine in the six months prior to 1 March 2020. Between 1 March 2020 and 13 July 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0.23% (95% CI 0.18–0.29) among users and 0.22% (95% CI 0.20–0.25) among non-users; an absolute difference of 0.008% (95% CI –0.051-0.066). After accounting for age, sex, ethnicity, use of other immunuosuppressives, and geographic region, no association with COVID-19 mortality was observed (HR 1.03, 95% CI 0.80–1.33). We found no evidence of interactions with age or other immunosuppressives. Quantitative bias analyses indicated observed associations were robust to missing information regarding additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality.ConclusionWe found no evidence of a difference in COVID-19 mortality among patients who received hydroxychloroquine for treatment of rheumatological disease prior to the COVID-19 outbreak in England.Research in contextEvidence before this studyPublished trials and observational studies to date have shown no evidence of benefit of hydroxychloroquine as a treatment for hospitalised patients who already have COVID-19. A separate question remains: whether routine ongoing use of hydroxychloroquine in people without COVID-19 protects against new infections or severe outcomes. We searched MEDLINE/PubMed for pharmacoepidemiological studies evaluating hydroxychloroquine for prevention of severe COVID-19 outcomes. The keywords “hydroxychloroquine AND (COVID OR coronavirus OR SARS-CoV-2) AND (prophyl* OR prevent*) AND (rate OR hazard OR odds OR risk)” were used and results were filtered to articles from the last year with abstracts available. 109 papers were identified for screening; none investigated pre-exposure prophylactic use of hydroxychloroquine for prevention of severe COVID-19 outcomes. Clinical trials of prophylactic use of hydroxychloroquine are ongoing; however, the largest trial does not expect to meet recruitment targets due to “…unjustified extrapolation and exaggerated safety concerns together with intense politicisation and negative publicity.” In the absence of reported clinical trials, evidence can be generated from real-world data to support the need for randomised clinical trials.Added value of this studyIn this cohort study representing 40% of the population of England, we investigated whether routine use of hydroxychloroquine prior to the COVID-19 outbreak prevented COVID-19 mortality. Using robust pharmacoepidemiological methods, we found no evidence to support a substantial benefit of hydroxychloroquine in preventing COVID-19 mortality. At the same time, we have shown no significant harm, and this generates the equipoise to justify continuing randomised trials. We have demonstrated in this study that it is feasible to address specific hypotheses about medicines in a rapid and transparent manner to inform interim clinical decision making and support the need for large-scale, randomised trial data.Implications of all the available evidenceThis is the first study to investigate the ongoing routine use of hydroxychloroquine and risk of COVID-19 mortality in a general population. While we found no evidence of any protective benefit, due to the observational nature of the study, residual confounding remains a possibility. Completion of trials for prevention of severe outcomes is warranted, but prior to the completion of these, we found no evidence to support the use of hydroxychloroquine for prevention of COVID-19 mortality.</jats:sec

Use of non-steroidal anti-inflammatory drugs and risk of death from COVID-19: an OpenSAFELY cohort analysis based on two cohorts.

OBJECTIVES: To assess the association between routinely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and deaths from COVID-19 using OpenSAFELY, a secure analytical platform. METHODS: We conducted two cohort studies from 1 March to 14 June 2020. Working on behalf of National Health Service England, we used routine clinical data in England linked to death data. In study 1, we identified people with an NSAID prescription in the last 3 years from the general population. In study 2, we identified people with rheumatoid arthritis/osteoarthritis. We defined exposure as current NSAID prescription within the 4 months before 1 March 2020. We used Cox regression to estimate HRs for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, accounting for age, sex, comorbidities, other medications and geographical region. RESULTS: In study 1, we included 536 423 current NSAID users and 1 927 284 non-users in the general population. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR 0.96, 95% CI 0.80 to 1.14) in the multivariable-adjusted model. In study 2, we included 1 708 781 people with rheumatoid arthritis/osteoarthritis, of whom 175 495 (10%) were current NSAID users. In the multivariable-adjusted model, we observed a lower risk of COVID-19 related death (HR 0.78, 95% CI 0.64 to 0.94) associated with current use of NSAID versus non-use. CONCLUSIONS: We found no evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about the routine therapeutic use of NSAIDs

OpenSAFELY: impact of national guidance on switching from warfarin to direct oral anticoagulants (DOACs) in early phase of COVID-19 pandemic in England

BackgroundEarly in the COVID-19 pandemic the NHS recommended that appropriate patients anticoagulated with warfarin should be switched to direct acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately co-prescribed two anticoagulants following a medication change, and associated monitoring.ObjectiveTo describe which people were switched from warfarin to DOACs; identify potentially unsafe co-prescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic.MethodsWorking on behalf of NHS England we conducted a population cohort based study using routine clinical data from &gt;17 million adults in England.Results20,000 of 164,000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in co-prescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. INR testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420).ConclusionsIncreased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people co-prescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic.</jats:sec

Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform

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