A comparison of four self-controlled study designs in an analysis of COVID-19 vaccines and myocarditis using five European databases (preprint)

IntroductionThe aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis. MethodsWe used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures. ResultsWe included 1,757 cases of myocarditis. In unadjusted analyses, agreement between study designs varied by vaccine brand. There was good agreement between all designs for AstraZeneca and Pfizer, but for Moderna we found harmful incidence rate ratios (IRR) using the standard and extended SCCS (standard SCCS: IRR = 3.12, 95%CI = 1.53 - 6.40; extended SCCS: IRR = 2.43, 95%CI = 1.11 - 5.33) compared with no association with the SCRIs (SCRI-pre: IRR = 0.60, 95%CI = 0.27 - 1.33; SCRI-post: IRR = 0.86, 95%CI = 0.34 - 2.19), although confidence intervals were wide. There was very good agreement between all designs for the unadjusted second dose analyses, confirming the known harmful association between the second dose of Moderna and Pfizer vaccines and myocarditis. ConclusionsIn the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures.

Comparative effectiveness of sotrovimab and molnupiravir for preventing severe COVID-19 outcomes in non-hospitalised patients on kidney replacement therapy: observational cohort study using the OpenSAFELY-UKRR linked platform and SRR database (preprint)

Background Patients on kidney replacement therapy (KRT; dialysis and kidney transplantation) are at the highest risk of severe outcomes from COVID-19. Due to limited inclusion of patients on KRT in clinical trials, information is limited on the effectiveness of sotrovimab (a neutralising monoclonal antibody). We sought to address this by comparing its effectiveness against molnupiravir (an antiviral) in preventing severe COVID-19 outcomes in non-hospitalised adults with symptomatic COVID-19. Methods With the approval of NHS England we used routine clinical data from 24 million patients in England linked to the UK Renal Registry (UKRR) to identify patients on KRT, and data on antiviral treatments, COVID-19 test results, hospitalisation events and death from the OpenSAFELY-TPP data resource. Cox proportional hazards models (stratified for region) were used to estimate hazard ratios of sotrovimab vs. molnupiravir with regards to COVID-19 related hospitalisation or deaths in the subsequent 28 days (as the primary outcome). Further analyses were conducted using propensity score weighting (adjusted for region) and to investigate robustness of results with regards to different time periods, missing data, and adjustment variables. We also conducted a complementary analysis using data from patients in the Scottish Renal Registry (SRR) treated with sotrovimab or molnupiravir, following similar analytical approaches. Results Among the 2367 renal patients treated with sotrovimab (n=1852) or molnupiravir (n=515) between December 16, 2021 and August 1, 2022 in England, 38 cases (1.6%) of COVID-19 related hospitalisations/deaths were observed during the 28 days of follow-up after treatment initiation, with 21 (1.1%) in the sotrovimab group and 17 (3.3%) in the molnupiravir group. In multiple-adjusted analysis sotrovimab was associated with substantially lower risk of 28-day COVID-19 related hospitalisation/death than treatment with molnupiravir (hazard ratio, HR=0.35, 95% CI: 0.17 to 0.71; P=0.004), with results remaining robust in sensitivity analyses. In the SRR cohort, there were 19 cases (1.9%) of COVID-19 related hospitalisations/deaths during the 28 days of follow-up after treatment initiation of sotrovimab (n=723) or molnupiravir (n=270). In multiple-adjusted analysis, sotrovimab showed a trend toward lower risk of 28-day COVID-19 related hospitalisation/death than treatment with molnupiravir (HR=0.40, 95% CI: 0.13 to 1.21; P=0.106). In both datasets, sotrovimab had no evidence of association with other hospitalisation/death compared with molnupiravir (HRs ranging from 0.73-1.20; P>0.05). Conclusions In routine care of non-hospitalised patients with COVID-19 on kidney replacement therapy, those who received sotrovimab had substantially lower risk of severe COVID-19 outcomes than those receiving molnupiravir.

OpenSAFELY: Risks of COVID-19 hospital admission and death for people with learning disabilities - a cohort study. (preprint)

ObjectivesTo assess the association between learning disability and risk of hospitalisation and mortality from COVID-19 in England among adults and children. DesignWorking on behalf of NHS England, two cohort studies using patient-level data for >17 million people from primary care electronic health records were linked with death data from the Office for National Statistics and hospitalization data from NHS Secondary Uses Service using the OpenSAFELY platform. SettingGeneral practices in England which use TPP software. ParticipantsParticipants were males and females, aged up to 105 years, from two cohorts: (1) wave 1, registered with a TPP practice as of 1st March 2020 and followed until 31st August, 2020; (2) wave 2 registered 1st September 2020 and followed until 31st December 2020 (for admissions) or 8th February 2021 (for deaths). The main exposure group was people included on a general practice learning disability register (LDR), with a subgroup of people classified as having profound or severe learning disability. We also identified patients with Down syndrome and cerebral palsy (whether or not on the learning disability register). Main outcome measures(i) COVID-19 related death, (ii) COVID-19 related hospitalisation. Non-COVID-19 related death was also explored. ResultsIn wave 1, of 14,301,415 included individuals aged 16 and over, 90,095 (0.63%) were identified as being on the LDR. 30,173 COVID-related hospital admissions, 13,919 COVID-19 related deaths and 69,803 non-COVID deaths occurred; of which 538 (1.8%), 221 (1.6%) and 596 (0.85%) were among individuals on the LDR, respectively. In wave 2, 27,611 COVID-related hospital admissions, 17,933 COVID-19 related deaths and 54,171 non-COVID deaths occurred; of which 383 (1.4%), 260 (1.4%) and 470 (0.87%) were among individuals on the LDR. Wave 1 hazard ratios for individuals on the LDR, adjusted for age, sex, ethnicity and geographical location, were 5.3 (95% confidence interval (CI) 4.9, 5.8) for COVID-19 related hospital admissions and 8.2 (95% CI: 7.1, 9.4) for COVID-19 related death. Wave 2 produced similar estimates. Associations were stronger among those classed as severe-profound and among those in residential care. Down syndrome and cerebral palsy were associated with increased hazard of both events in both waves; Down syndrome to a much greater extent. Hazards of non-COVID-19 related death followed similar patterns with weaker associations. ConclusionsPeople with learning disabilities have markedly increased risks of hospitalisation and mortality from COVID-19. This raised risk is over and above that seen for non-COVID causes of death. Ensuring prompt access to Covid-19 testing and health care and consideration of prioritisation for COVID-19 vaccination and other targeted preventive measures are warranted.

Predicting COVID-19 related death using the OpenSAFELY platform (preprint)

Objectives To compare approaches for obtaining relative and absolute estimates of risk of 28-day COVID-19 mortality for adults in the general population of England in the context of changing levels of circulating infection. Design Three designs were compared. (A) case-cohort which does not explicitly account for the time-changing prevalence of COVID-19 infection, (B) 28-day landmarking, a series of sequential overlapping sub-studies incorporating time-updating proxy measures of the prevalence of infection, and (C) daily landmarking. Regression models were fitted to predict 28-day COVID-19 mortality. Setting Working on behalf of NHS England, we used clinical data from adult patients from all regions of England held in the TPP SystmOne electronic health record system, linked to Office for National Statistics (ONS) mortality data, using the OpenSAFELY platform. Participants Eligible participants were adults aged 18 or over, registered at a general practice using TPP software on 1st March 2020 with recorded sex, postcode and ethnicity. 11,972,947 individuals were included, and 7,999 participants experienced a COVID-19 related death. The study period lasted 100 days, ending 8th June 2020. Predictors A range of demographic characteristics and comorbidities were used as potential predictors. Local infection prevalence was estimated with three proxies: modelled based on local prevalence and other key factors; rate of A&E COVID-19 related attendances; and rate of suspected COVID-19 cases in primary care. Main outcome measures COVID-19 related death. Results All models discriminated well between patients who did and did not experience COVID-19 related death, with C-statistics ranging from 0.92-0.94. Accurate estimates of absolute risk required data on local infection prevalence, with modelled estimates providing the best performance. Conclusions Reliable estimates of absolute risk need to incorporate changing local prevalence of infection. Simple models can provide very good discrimination and may simplify implementation of risk prediction tools in practice.

OpenSAFELY: Do adults prescribed Non-steroidal anti-inflammatory drugs have an increased risk of death from COVID-19? (preprint)

Importance: There has been speculation that non-steroidal anti-inflammatory drugs (NSAIDs) may negatively affect coronavirus disease 2019 (COVID-19) outcomes, yet clinical evidence is limited. Objective: To assess the association between NSAID use and deaths from COVID-19 using OpenSAFELY, a secure analytical platform. Design: Two cohort studies (1st March-14th June 2020). Setting: Working on behalf of NHS England, we used routine clinical data from >17 million patients in England linked to death data from the Office for National Statistics. Participants: Study 1: General population (people with an NSAID prescription in the last three years). Study 2: people with rheumatoid arthritis/osteoarthritis. Exposures: Current NSAID prescription within the 4 months before 1st March 2020. Main Outcome and Measure: We used Cox regression to estimate hazard ratios (HRs) for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, adjusting for age, sex, comorbidities and other medications. Results: In Study 1, we included 535,519 current NSAID users and 1,924,095 non-users in the general population. The crude HR for current use was 1.25 (95% CI, 1.07-1.46), versus non-use. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR, 0.95, 95% CI, 0.80-1.13) in the fully adjusted model. In Study 2, we included 1,711,052 people with rheumatoid arthritis/osteoarthritis, of whom 175,631 (10%) were current NSAID users. The crude HR for current use was 0.43 (95% CI, 0.36-0.52), versus non-use. In the fully adjusted model, we observed a lower risk of COVID-19 related death (HR, 0.78, 95% CI, 0.65-0.94) associated with current use of NSAID versus non-use. Conclusion and Relevance: We found no evidence of a harmful effect of NSAIDs on COVID-19 related deaths. Risks from COVID-19 do not need to influence decisions about therapeutic use of NSAIDs.