Abstract Objectives To quantify in absolute and relative terms how population-level COVID-19 death rates have changed in demographic and clinical subgroups. Design Retrospective cohort study on behalf of NHS England. Setting Linked primary care and death registry data from the OpenSAFELY-TPP platform, covering the first three pandemic waves in England (wave 1: March 23 to May 30, 2020; wave 2: September 7, 2020 to April 24, 2021; and wave 3, delta: May 28 to December 14, 2021). Participants In total, 18.7, 18.8, and 18.7 million adults were included for waves 1, 2, and 3 respectively. Main outcome measures COVID-19-related mortality based on linked death registry records. Results The crude absolute COVID-19-related death rate per 1,000 person-years decreased from 4.48 in wave 1 (95%CI 4.41;4.55), to 2.70 in wave 2 (95%CI 2.67;2.73), to 0.64 in wave 3 (95%CI 0.63;0.66). The absolute death rate decreased by 90% between waves 1 and 3 in patients aged 80+, but by only 20% in patients aged 18-39. This higher proportional reduction in age- and sex-standardised death rates was also seen for other groups, such as neurological disease, learning disability and severe mental illness. Conversely, standardised death rates in transplant recipients stayed constant across successive waves at 10 per 1,000 person-years. There was also only a small decrease in death rates between waves in people with kidney disease, haematological malignancies or conditions associated with immunosuppression. Consequently, the relative hazard of COVID-19-related death decreased over time for some variables (e.g. age), remained similar for some (e.g. sex, ethnicity), and increased for others (e.g. transplant). Conclusions COVID-19 death rates decreased over the first three pandemic waves. An especially large decrease was seen in older age groups and people with neurological disease, learning disability or severe mental illness. Some demographic inequalities in death rates persisted over time. Groups more likely to experience impaired vaccine effectiveness did not see the same benefit in COVID-19 mortality reduction.
Abstract Background The investigation of suspected subarachnoid haemorrhage (SAH) presents a diagnostic dilemma. The limited sensitivity of a negative CT brain scan has historically mandated hospital admission and a lumbar puncture to look for evidence of blood in the cerebrospinal fluid. However, emerging evidence has suggested the sensitivity of clinical decision rules and modern CT imaging protocols within early onset of symptoms, may be sufficient to exclude the diagnosis. Methods A prospective, multi-centre, observational study of consecutive adult patients with acute severe non-traumatic headache presenting to emergency departments. We plan to recruit 9000 patients from over a hundred sites across the UK. The primary outcome is adjudicated SAH as defined by neuroimaging or cerebrospinal fluid findings consistent with the diagnosis. Data will be collected on clinical history, examination findings, phlebotomy and imaging results. All participants will be followed for 28-days to identify SAH and other clinically relevant outcomes using case note review, and later Hospital Episode Statistics. A proportionate opt-out model of consent will be used to maximise patient recruitment and study generalisability. Discussion Whilst there is increasing evidence that early neuroimaging strategies for the diagnosis of SAH are very sensitive, there have been no large studies to confirm this in the UK population. Furthermore, the test characteristics of CT brain beyond 6 hours from onset are not well understood and there is limited biological plausibility for this defined time cutpoint. Finally, the performance of the Ottawa clinical decision rule has shown promise in the Canadian population. However, its performance in the UK has not been studied and there are concerns that due to the low specificity it may result in increased, rather than decreased rate of investigations. This study will therefore aim to assess the test characteristics of both a CT brain up to 24h from presentation and the Ottawa SAH clinical decision rule.
Abstract 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.
Abstract Background The pandemic accelerated work by the NHS in England to enable and stimulate use of online consultation systems across all practices, for improved access to primary care. Objective We aimed to explore general practice coding activity associated with the use of online consultation systems in terms of trends, COVID-19 effect, variation and quality. Methods With the approval of NHS England, OpenSAFELY-TPP and OpenSAFELY-EMIS were used to query and analyse in situ records of electronic health record systems of over 53 million patients in over 6,400 practices, mainly in 2019-2020. SNOMED CT codes relevant to online consultation systems and written online consultations were identified. Coded events were described by volumes, practice coverage, trends pre- and post-COVID-19 and inter-practice and sociodemographic variation. Results 3,550,762 relevant coding events were found in TPP practices, with code eConsultation detected in 84% of practices. Coding activity related to digital forms of interaction increased rapidly from March 2020 at the onset of the COVID-19 pandemic, though we found large variation in coding instance rates among practices in England. Code instances were more commonly found among females, those aged 18-40, those least deprived or white. eConsultation coded activity was more commonly found recorded among patients with a history of asthma or depression. Conclusions We successfully queried general practice coding activity relevant to the use of online consultation systems, showing increased adoption as well as key areas of variation during the COVID-19 pandemic. The work can be expanded to support monitoring of coding quality and underlying activity. In future, large-scale impact evaluation studies can be implemented within the platform, namely looking at resource utilisation and patient outcomes.
Aims The COVID‐19 pandemic caused significant disruption to routine activity in primary care. Medication reviews are an important primary care activity ensuring safety and appropriateness of prescribing. A disruption could have significant negative implications for patient care. Using routinely collected data, our aim was first to describe codes used to record medication review activity and then to report the impact of COVID‐19 on the rates of medication reviews. Methods With the approval of NHS England, we conducted a cohort study of 20 million adult patient records in general practice, in‐situ using the OpenSAFELY platform. For each month, between April 2019 and March 2022, we report the percentage of patients with a medication review coded monthly and in the previous 12 months with breakdowns by regional, clinical and demographic subgroups and those prescribed high‐risk medications. Results In April 2019, 32.3% of patients had a medication review coded in the previous 12 months. During the first COVID‐19 lockdown, monthly activity decreased (−21.1% April 2020), but the 12‐month rate was not substantially impacted (−10.5% March 2021). The rate of structured medication review in the last 12 months reached 2.9% by March 2022, with higher percentages in high‐risk groups (care home residents 34.1%, age 90+ years 13.1%, high‐risk medications 10.2%). The most used medication review code was Medication review done 314530002 (59.5%). Conclusions There was a substantial reduction in the monthly rate of medication reviews during the pandemic but rates recovered by the end of the study period. Structured medication reviews were prioritized for high‐risk patients.
Abstract 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=0.39, 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 0.73-1.29; 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.
Abstract Background The effectiveness of COVID-19 monoclonal antibody and antiviral therapies against severe COVID-19 outcomes is unclear. Initial benefit was shown in unvaccinated patients and before the Omicron variant emerged. We used the OpenSAFELY platform to emulate target trials to estimate the effectiveness of sotrovimab or molnupiravir, versus no treatment. Methods With the approval of NHS England, we derived population-based cohorts of non-hospitalised high-risk individuals in England testing positive for SARS-CoV-2 during periods of dominance of the BA.1 (16/12/2021-10/02/2022) and BA.2 (11/02/2022-21/05/2022) Omicron sublineages. We used the clone-censor-weight approach to estimate the effect of treatment with sotrovimab or molnupiravir initiated within 5 days after positive test versus no treatment. Hazard ratios (HR) for COVID-19 hospitalisation or death within 28 days were estimated using weighted Cox models. Results Of the 35,856 [BA.1 period] and 39,192 [BA.2 period] patients, 1,830 [BA.1] and 1,242 [BA.2] were treated with molnupiravir and 2,244 [BA.1] and 4,164 [BA.2] with sotrovimab. The estimated HRs for molnupiravir versus untreated were 1.00 (95%CI: 0.81;1.22) [BA.1] and 1.22 (0.96;1.56) [BA.2]; corresponding HRs for sotrovimab versus untreated were 0.76 (0.66;0.89) [BA.1] and 0.92 (0.79;1.06) [BA.2]. Interpretation Compared with no treatment, sotrovimab was associated with reduced risk of adverse outcomes after COVID-19 in the BA.1 period, but there was weaker evidence of benefit in the BA2 period. Molnupiravir was not associated with reduced risk in either period. Funding UKRI, Wellcome Trust, MRC, NIHR and HDRUK.
Due to limited inclusion of patients on kidney replacement therapy (KRT) in clinical trials, the effectiveness of coronavirus disease 2019 (COVID-19) therapies in this population remains unclear. We sought to address this by comparing the effectiveness of sotrovimab against molnupiravir, two commonly used treatments for non-hospitalised KRT patients with COVID-19 in the UK.
Abstract Background Long COVID is a major problem affecting patient health, the health service, and the workforce. To optimise the design of future interventions against COVID-19, and to better plan and allocate health resources, it is critical to quantify the health and economic burden of this novel condition. Methods With the approval of NHS England, we developed OpenPROMPT, a UK cohort study measuring the impact of long COVID on health-related quality-of-life (HRQoL). OpenPROMPT invited responses to Patient Reported Outcome Measures (PROMs) using a smartphone application and recruited between November 2022 and October 2023. We used the validated EuroQol EQ-5D questionnaire with the UK Value Set to develop disutility scores (1-utility) for respondents with and without Long COVID using linear mixed models, and we calculated subsequent Quality-Adjusted Life-Months (QALMs) for long COVID. Results We used data from 6,070 participants where 24.7% self-reported long COVID. In multivariable regressions, long COVID had a consistent impact on HRQoL, showing a high probability of reporting loss in quality-of-life (OR: 22, 95% CI:12.35-39.29) compared with people who did not report long COVID. Reporting a disability was the largest predictor of losses of HRQoL (OR: 60.2, 95% CI: 27.79-130.57) across survey responses. Self-reported long COVID was associated with an 0.37 QALM loss. Conclusions We found substantial impacts on quality-of-life due to long COVID, representing a major burden on patients and the health service. We highlight the need for continued support and research for long COVID, as HRQoL scores compared unfavourably to patients with conditions such as multiple sclerosis, heart failure, and renal disease.
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