Changes in opioid prescribing during the COVID-19 pandemic in England: cohort study of 20 million patients in OpenSAFELY-TPP (preprint)

Background: The COVID-19 pandemic led to disruptions in healthcare delivery, including postponement of elective procedures and difficulty accessing in-person care, which may have increased the need for strong pharmacological pain relief in some patients. Methods: With NHS England approval, we used routine clinical data from >20 million general practice adult patients in OpenSAFELY-TPP. We used interrupted time series analysis to quantify trends in prevalent and incident opioid prescribing prior to the pandemic (January 2018-February 2020) and changes during the COVID-19 lockdown period (March 2020-March 2021) and recovery period (April 2021-June 2022). We identified how these changes varied in people living in care homes, and by age, sex, deprivation, ethnicity, and geographic region. Results: The median number of people prescribed an opioid per month was 50.9 per 1000 patients prior to the pandemic. We observed little change in overall prescribing after the start of the pandemic, except for a temporary increase in March 2020. There was a 9.8% (95%CI -14.5%, -6.5%) reduction in new opioid prescribing from March 2020, sustained to the end of the study period. Reductions in new prescribing were observed for all demographics except people 80+ years. Among care home residents, in April 2020 new opioid prescribing increased by 112.5% (95%CI 92.2%, 134.9%) and parenteral opioid prescribing increased by 186.3% (95%CI 153.1%, 223.9%). Conclusion: Changes in opioid prescribing during the COVID-19 pandemic were mostly consistent across subgroups with the exception of differences by age and care home residence. Among people in care homes, increases in parenteral opioid prescribing likely reflect use to treat end-of-life COVID-19 symptoms. Further research is needed to understand what is driving the reduction in new opioid prescribing and its relation to changes to health care provision during the pandemic.

Clinical coding of long COVID in primary care 2020-2023 in a cohort of 19 million adults: an OpenSAFELY analysis (preprint)

Background Long COVID is the patient-coined term for the persistent symptoms of COVID-19 illness for weeks, months or years following the acute infection. There is a large burden of long COVID globally from self-reported data, but the epidemiology, causes and treatments remain poorly understood. Primary care is used to help identify and treat patients with long COVID and therefore Electronic Health Records (EHRs) of past COVID-19 patients could be used to help fill these knowledge gaps. We aimed to describe those with long COVID in primary care records in England. Methods With the approval of NHS England we used routine clinical data from over 19 million adults in England linked to SARS-COV-2 test result, hospitalisation and vaccination data to describe trends in the recording of 16 clinical codes related to long COVID between November 2020 and January 2023. We calculated rates per 100,000 person-years and plotted how these changed over time. We compared crude and minimally adjusted rates of recorded long COVID in patient records between different key demographic and vaccination characteristics using negative binomial models. Findings We identified a total of 55,465 people recorded to have long COVID over the study period, with incidence of new long COVID records increasing steadily over 2021, and declining over 2022. The overall rate per 100,000 person-years was 177.5 cases in women (95% CI: 175.5-179) and 100.5 men (99.5-102). In terms of vaccination against COVID-19, the lowest rates were observed in those with 3+ vaccine doses (103.5 [95% CI: 101.5-105]). Finally, the majority of those with a long COVID record did not have a recorded positive SARS-COV-2 test 12 weeks before the long COVID record. Interpretation EHR recorded long COVID remains very low compared and incident records of long COVID declined over 2022. We found the lowest rates of recorded long COVID in people with 3 or more vaccine doses. We summarised several sources of possible bias for researchers using EHRs to study long COVID. Funding This research was supported by the National Institute for Health and Care Research (NIHR) (OpenPROMPT: COV-LT2-0073))

Effect of the 2022 COVID-19 booster vaccination campaign in 50 year olds in England: regression discontinuity analysis in OpenSAFELY (preprint)

Background: SARS-CoV-2 vaccines are highly effective in preventing severe COVID-19 but require boosting to maintain protection. Changes to circulating variants and prevalent natural immunity may impact on real-world effectiveness of boosters in different time periods and in different populations. Methods: With NHS England approval, we used linked routine clinical data from >24 million patients to evaluate the effectiveness of the 2022 combined COVID-19 autumn booster and influenza vaccine campaign in non-clinically vulnerable 50-year-olds in England using a regression discontinuity design. Our primary outcome was a composite of 6-week COVID-19 emergency attendance, COVID-19 unplanned hospitalisation, or death. The secondary outcomes were: respiratory hospitalisations or death; any unplanned hospitalisation; and any death. Results: Our study included 1,917,375 people aged 45-54 years with no evidence of being in a high-risk group prioritised for vaccination. By 26 November 2022, booster vaccine coverage was 11.1% at age 49.75 years increasing to 39.7% at age 50.25 years. The estimated effect of the campaign on the risk of the primary outcome in 50-year-olds during weeks 7-12 after the campaign start was -0.4 per 100,000 (95% CI -7.8, 7.1). For the secondary outcomes the estimated effects were: -0.6 per 100,000 (95%CI -13.5, 12.3) for respiratory outcomes; 5.0 per 100,000 (95%CI -40.7, 50.8) for unplanned hospitalisations; and 3.0 per 100,000 (95%CI -2.7, 8.6) for any death. The results were similar when using different follow-up start dates, different bandwidths, or when estimating the effect of vaccination (rather than the campaign). Conclusion: This study found little evidence that the autumn 2022 vaccination campaign in England was associated with a reduction in severe COVID-19-related outcomes among non-clinically vulnerable 50-year-olds. Possible explanations include the low risk of severe outcomes due to substantial pre-existing vaccine- and infection-induced immunity. Modest booster coverage reduced the precision with which we could estimate effectiveness. The booster campaign may have had effects beyond those estimated, including reducing virus transmission and incidence of mild or moderate COVID-19.

Fit notes associated with COVID-19 in 24 million patients' primary care records: A cohort study in OpenSAFELY-TPP (preprint)

Background: Fit notes ("sick notes") are issued by general practitioners (GPs) when a person can't work for health reasons and is an indication of the public health and economic burden for people recovering from COVID-19. Methods: With NHS England approval, we used routine clinical data from >24 million patients to compare fit note incidence in people 18-64 years with and without evidence of COVID-19 in 2020, 2021 and 2022. We fit Cox regression models to estimate adjusted hazard ratios, overall and by time post-diagnosis and within demographic subgroups. Results: We identified 365,421, 1,206,555 and 1,321,313 people with evidence of COVID-19 in 2020, 2021 and 2022. The fit note rate was 4.88 per 100 person-months (95%CI 4.83-4.93) in 2020, 2.66 (95%CI 2.64-2.67) in 2021, and 1.73 (95%CI 1.72-1.73) in 2022. Compared with the age, sex and region matched general population, the hazard ratio (HR) adjusted for demographics and clinical characteristics over the follow-up period was 4.07 (95%CI 4.02-4.12) in 2020 decreasing to 1.57 (95%CI 1.56-1.58) in 2022. The HR was highest in the first 30 days in all years. Conclusions: Despite likely underestimation of the fit note rate, we identified a considerable increase among people with COVID-19, even in an era when most people are vaccinated. Most fit notes are associated with the acute phase of the disease, but the increased risk several months post-diagnosis provides further evidence of the long-term impact.

The impact of COVID-19 on medication reviews in English primary care. An OpenSAFELY-TPP analysis of 20 million adult electronic health records. (preprint)

Background The COVID-19 pandemic caused significant disruption to routine activity in primary care. Medication reviews are an important primary care activity to ensure safety and appropriateness of ongoing prescribing and a disruption could have significant negative implications for patient care. Aim Using routinely collected data, our aim was to i) describe the SNOMED CT codes used to report medication review activity ii) report the impact of COVID-19 on the volume and variation of medication reviews. Design and setting 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. Method For each month between April 2019 - March 2022, we report the percentage of patients with a medication review coded monthly and in the previous 12 months. These measures were broken down by regional, clinical and demographic subgroups and amongst 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 substantially decreased (-21.1% April 2020), but the rate of patients with a medication review coded in the previous 12 months was not substantially impacted according to our classification (-10.5% March 2021). There was regional and ethnic variation (March 2022 - London 21.9% vs North West 33.6%; Chinese 16.8% vs British 33.0%). Following the introduction of "structured medication reviews", the rate of structured medication review in the last 12 months reached 2.9% by March 2022, with higher percentages in high risk groups (March 2022 - care home residents 34.1%, 90+ years 13.1%, high risk medications 10.2%). The most used SNOMED CT medication review code across the study period was Medication review done - 314530002 (59.5%). Conclusion We have reported a substantial reduction in the monthly rate of medication reviews during the pandemic but rates recovered by the end of the study period.

Impact of COVID-19 on recorded blood pressure screening and hypertension management in England: An analysis of monthly changes in Quality and Outcomes Framework indicators in OpenSAFELY (preprint)

Background: Cardiovascular disease management in primary care in England was disrupted during the COVID-19 pandemic. Objective: We aim to describe the impact of the COVID-19 pandemic on blood pressure screening and hypertension management, based upon a national quality of care scheme (Quality and Outcomes Framework, QOF) across key demographic, regional, and clinical subgroups. To this end, we translate complex clinical quality of care schemes from text descriptions into reusable analytic code. Methods: With the approval of NHS England, a population based cohort study was conducted on 25.2 million patient records in situ using OpenSAFELY-TPP. We included all NHS patients registered at general practices using TPP software between March 2019 and March 2023. Individuals that were eligible for blood pressure screening and with a diagnosis of hypertension were identified according to the QOF 2021/22 business rules. We examined monthly changes in recorded blood pressure screening in the preceding 5 years in patients aged [≥] 45, recorded hypertension prevalence, and the recorded percentage of patients treated to target (i.e., [≤] 140/90 mmHg for patients [≤] 79 years and [≤] 150/90 mmHg for patients [≥] 80 years) in the preceding 12 months, within demographic, regional, and clinical subgroups as well as the variation across practices. Results: The overall percentage of patients aged [≥] 45 who had blood pressure screening recorded in the preceding 5 years decreased from 90% in March 2019 to 85% in March 2023. Recorded hypertension prevalence was relatively stable at 15% throughout the study period. The percentage of patients with a record of hypertension treated to target in the preceding 12 months reduced from a maximum of 71% in March 2020 to a minimum of 47% in February 2021 in patients aged [≤] 79 years, and from 85% in March 2020 to a minimum of 58% in February 2021 in patients aged [≥] 80 years before recovering. Blood pressure screening rates in the preceding 5 years remained stable in older age groups, patients with a record of learning disability, or care home status. Conclusions: There was substantial disruption to hypertension management QOF indicators during the pandemic, which can likely be attributed to a general reduction of blood pressure screening. OpenSAFELY can be used to continuously monitor monthly changes in national quality of care schemes to identify changes in key clinical subgroups early and support prioritisation of recovery from disrupted care caused by COVID-19.

Patient characteristics associated with clinically coded long COVID: an OpenSAFELY study using electronic health records (preprint)

Despite reports of post-COVID-19 syndromes (long COVID) are rising, clinically coded long COVID cases are incomplete in electronic health records. It is unclear how patient characteristics may be associated with clinically coded long COVID. With the approval of NHS England, we undertook a cohort study using electronic health records within the OpenSAFELY-TPP platform in England, to study patient characteristics associated with clinically coded long COVID from 29 January 2020 to 31 March 2022. We estimated age-sex adjusted hazard ratios and fully adjusted hazard ratios for coded long COVID. Patient characteristics included demographic factors, and health behavioural and clinical factors. Among 17,986,419 adults, 36,886 (0.21%) were clinically coded with long COVID. Patient characteristics associated with coded long COVID included female sex, younger age (under 60 years), obesity, living in less deprived areas, ever smoking, greater consultation frequency, and history of diagnosed asthma, mental health conditions, pre-pandemic post-viral fatigue, or psoriasis. The strength of these associations was attenuated following two-dose vaccination compared to before vaccination. The incidence of coded long COVID was higher after hospitalised than non-hospitalised COVID-19. These results should be interpreted with caution given that long COVID was likely under-recorded in electronic health records.

OpenSAFELY: The impact of COVID-19 on azathioprine, leflunomide, and methotrexate monitoring, and factors associated with change in monitoring rate. (preprint)

Background: The COVID-19 pandemic created unprecedented pressure on healthcare services. This study aimed to investigate if disease-modifying anti-rheumatic drug (DMARD) safety monitoring was affected during the COVID-19 pandemic. Methods: A population-based cohort study was conducted with the approval of NHS England, using the OpenSAFELY platform to access electronic health record data from 24.2 million patients registered at general practices using TPP's SystmOne software. Patients were included for further analysis if prescribed azathioprine, leflunomide, or methotrexate between November 2019 and July 2022. Outcomes were assessed as monthly trends and variation between various sociodemographic and clinical groups for adherence with standard safety monitoring recommendations. Findings: An acute increase in the rate of missed monitoring occurred across the study population (+12.4 percentage points) when lockdown measures were implemented in March 2020. This increase was more pronounced for some patient groups (70-79 year-olds: +13.7 percentage points; females: +12.8 percentage points), regions (North West: +17.0 percentage points), medications (Leflunomide: +20.7 percentage points), and monitoring tests (Blood Pressure: +24.5 percentage points). Missed monitoring rates decreased substantially for all groups by July 2022. Substantial and consistent differences were observed in overall missed monitoring rates between several groups throughout the study. Interpretation: DMARD monitoring rates temporarily deteriorated during the COVID-19 pandemic. Deterioration coincided with the onset of lockdown measures, with monitoring rates recovering rapidly as lockdown measures were eased. Differences observed in monitoring rates between medications, tests, regions, and patient groups, highlight opportunities to tackle potential inequalities in the provision or uptake of monitoring services. Further research should aim to evaluate the causes of the differences identified between groups. Funding: None. Keywords COVID-19, electronic health records, general practice, primary health care, antirheumatic agents, methotrexate, azathioprine, leflunomide.

Healthcare in England was affected by the COVID-19 pandemic across the pancreatic cancer pathway: a cohort study using OpenSAFELY-TPP (preprint)

Background Healthcare across all sectors, in the UK and globally, was negatively affected by the COVID-19 pandemic. We investigated the effect of the COVID-19 pandemic on the quantity of healthcare services delivered to people with pancreatic cancer. Methods With the approval of NHS England, and drawing from a nationally representative OpenSAFELY-TPP dataset of 24 million patients (over 40% of the English population), we undertook a cohort study of people diagnosed with pancreatic cancer. We queried electronic healthcare records for information on the provision of healthcare services across the pancreatic cancer pathway. To estimate the effect of the COVID-19 pandemic, we predicted the rates of healthcare services if the pandemic had not happened. We used generalised linear models (GLM) and the pre-pandemic data from January 2015 to February 2020 to predict rates in March 2020 to September 2022. The 95% confidence intervals of the predicted values were used to estimate the significance of the difference between the predicted and observed rates. Results The rate of pancreatic cancer and diabetes diagnoses in the cohort was not affected by the pandemic. There were 24,500 people diagnosed with pancreatic cancer from January 2015 to September 2022. The mean age at diagnosis was 72 (SD 11), 48% of people were female, 95% were of White ethnicity and 39% were diagnosed with diabetes. We found a reduction in surgical resections by nearly 25% during the pandemic. In addition, 20%, 10% and 5% fewer people received BMI, HbA1c and liver function tests respectively before they were diagnosed with pancreatic cancer. There was no impact of the pandemic on the number of people making contact with primary care, but the number of contacts increased on average by 1 to 2 per person amongst those who made contact. Abdominal scans decreased by 7% and reporting of jaundice decreased by 20%, but recovered within six months into the pandemic. Emergency department visits, hospital admissions and deaths were not affected. Conclusions The pandemic affected healthcare in England across the pancreatic cancer pathway. Positive lessons could be learnt from services that recovered quickly. The reductions in healthcare experienced by people with cancer have the potential to lead to worse outcomes. Current efforts should focus on addressing the unmet needs of people with cancer.

Eleven key measures for monitoring general practice clinical activity during COVID-19 using federated analytics on 48 million adults' primary care records through OpenSAFELY (preprint)

Background The COVID-19 pandemic has had a significant impact on delivery of NHS care. We have developed the OpenSAFELY Service Restoration Observatory (SRO) to describe this impact on primary care activity and monitor its recovery. Objectives To develop key measures of primary care activity and describe the trends in these measures throughout the COVID-19 pandemic. Methods With the approval of NHS England we developed an open source software framework for data management and analysis to describe trends and variation in clinical activity across primary care electronic health record (EHR) data on 48 million adults. We developed SNOMED-CT codelists for key measures of primary care clinical activity selected by a expert clinical advisory group and conducted a population cohort-based study to describe trends and variation in these measures January 2019-December 2021, and pragmatically classified their level of recovery one year into the pandemic using the percentage change in the median practice level rate. Results We produced 11 measures reflective of clinical activity in general practice. A substantial drop in activity was observed in all measures at the outset of the COVID-19 pandemic. By April 2021, the median rate had recovered to within 15% of the median rate in April 2019 in six measures. The remaining measures showed a sustained drop, ranging from a 18.5% reduction in medication reviews to a 42.0% reduction in blood pressure monitoring. Three measures continued to show a sustained drop by December 2021. Conclusions The COVID-19 pandemic was associated with a substantial change in primary care activity across the measures we developed, with recovery in most measures. We delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. We will continue to expand the set of key measures to be routinely monitored using our publicly available NHS OpenSAFELY SRO dashboards with near real-time data.

Changes in COVID-19-related mortality across key demographic and clinical subgroups: an observational cohort study using the OpenSAFELY platform on 18 million adults in England (preprint)

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 rate of COVID-19-related death 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 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 death rates was also seen for other groups, such as neurological disease, learning disability and severe mental illness. Conversely, 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.

The impact of COVID-19 on prescribing of pancreatic enzyme replacement therapy for people with unresectable pancreatic cancer in England. A cohort study using OpenSafely-TPP (preprint)

Background: Cancer treatments were variably disrupted during the COVID-19 pandemic. Despite UK national guidelines recommending pancreatic enzyme replacement therapy to all people with unresectable pancreatic cancer, observational studies demonstrate under-prescribing. Aim: To investigate the impact of the COVID-19 pandemic on the prescribing of pancreatic enzyme replacement to people with unresectable pancreatic cancer. Methods: With the approval of NHS England, we conducted a cohort study using 24 million health records through the OpenSAFELY-TPP research platform. We modelled the effect of COVID-19 with multivariable linear regression. Results: We found no reduction in pancreatic enzyme replacement therapy during the COVID-19 pandemic. Overall, since 2015, the rates of prescribing increased steadily over time by 1% every year. The national rates ranged from 41% in 2015 to 48% in 2022. There was substantial regional variation. The highest rates of 50% to 60% were in the West Midlands and lowest (20% to 30%) in London. Conclusions: In contrast to many other treatments, prescribing of pancreatic enzyme replacement therapy was not affected during the COVID-19 pandemic. Although overall rates increased over time, substantial under-prescribing existed at the end of this study (March 2022). At just under 50% in 2022, the rates were still below the recommended 100% standard. Prior work evaluating quality of care in this area relied on manual audits which come at increased cost and reduced frequency of updates. With the methodological advantage of OpenSAFELY, we established an automated audit which allows for regular updates.

OpenSAFELY: Representativeness of Electronic Health Record platform OpenSAFELY-TPP data compared to the population of England. (preprint)

BackgroundSince its inception in March 2020, data from the OpenSAFELY-TPP electronic health record platform has been used for more than 50 studies relating to the global COVID-19 emergency. OpenSAFELY-TPP data is derived from practices in England using SystmOne software, and has been used for the majority of these studies. We set out to investigate the representativeness of OpenSAFELY-TPP data by comparing it to national population estimates. MethodsWith the approval of NHS England, we describe the age, sex, Index of Multiple Deprivation and ethnicity of the OpenSAFELY-TPP population compared to national estimates from the Office for National Statistics. The five leading causes of death occurring between the 1st January 2020 and the 31st December 2020 were also compared to deaths registered in England during the same period. ResultsDespite regional variations, TPP is largely representative of the general population of England in terms of IMD (all within 1.1 percentage points), age, sex (within 0.1 percentage points), ethnicity and causes of death. The proportion of the five leading causes of death is broadly similar to those reported by ONS (all within 1 percentage point). ConclusionsData made available via OpenSAFELY-TPP is broadly representative of the English population. SummaryUsers of OpenSAFELY must consider the issues of representativeness, generalisability and external validity associated with using TPP data for health research. Although the coverage of TPP practices varies regionally across England, TPP registered patients are generally representative of the English population as a whole in terms of key demographic characteristics. Key messagesO_LIThere is regional variability across England in terms of key population characteristics C_LIO_LIUsers of OpenSAFELY should carefully consider the issues of representativeness, generalisability and external validity associated with using TPP data for health research. C_LIO_LITPP registered patients are a representative sub-sample of the English population as a whole in terms of age, sex, IMD and ethnicity. C_LIO_LIThe proportions of the five leading causes of death in TPP in 2020 are broadly similar to those reported by ONS. C_LI

Factors associated with COVID-19 vaccine uptake in people with kidney disease: an OpenSAFELY cohort study (preprint)

BackgroundKidney disease is a significant risk factor for COVID-19-related mortality. Achieving high COVID-19 vaccine coverage among people with kidney disease is therefore a public health priority. MethodsWith the approval of NHS England, we performed a retrospective cohort study using the OpenSAFELY-TPP platform. Individual-level routine clinical data from 24 million people in England were included. A cohort of individuals with stage 3-5 chronic kidney disease (CKD) or receiving renal replacement therapy (RRT) at the start of the COVID-19 vaccine roll-out was identified based on evidence of reduced estimated glomerular filtration rate or inclusion in the UK Renal Registry. Individual-level factors associated with vaccine uptake were explored via Cox proportional hazards models. Results948,845 people with stage 3-5 CKD or receiving RRT were included. Cumulative vaccine coverage as of 11th May 2022 was 97.5%, 97.0%, and 93.5% for doses 1, 2, and 3, respectively, and 61.1% among individuals with one or more indications for receipt of a fourth dose. Delayed 3-dose vaccine uptake was associated with non-White ethnicity, social deprivation, and severe mental illness - associations that were consistent across CKD stages and in RRT recipients. Similar associations were observed for 4-dose uptake, which was also delayed among care home residents. ConclusionAlthough high primary and booster dose coverage has been achieved among people with kidney disease in England, key disparities in vaccine uptake remain across demographic groups. Identifying how to address these disparities remains a priority to reduce the risk of severe disease in this vulnerable patient group.

Effectiveness of BNT162b2 booster doses in England: an observational study in OpenSAFELY-TPP (preprint)

Background The UK COVID-19 vaccination programme delivered its first "booster" doses in September 2021, initially in groups at high risk of severe disease then across the adult population. The BNT162b2 Pfizer-BioNTech vaccine was used initially, with Moderna mRNA-1273 subsequently also used. Methods We used the OpenSAFELY-TPP database, covering 40% of English primary care practices and linked to national coronavirus surveillance, hospital episodes, and death registry data, to estimate the effectiveness of boosting with BNT162b2 compared with no boosting in eligible adults who had received two primary course vaccine doses between 16 September and 16 December 2021 when the Delta variant of SARS-CoV-2 was dominant. Follow up was for up to 10 weeks. Each booster recipient was matched with an unboosted control on factors relating to booster priority status and prior immunisation. Additional factors were adjusted for in Cox models estimating hazard ratios (HRs). Outcomes were positive SARS-CoV-2 test, COVID-19 hospitalisation, COVID-19 death and non-COVID-9 death. Booster vaccine effectiveness was defined as 1-HR. Results Among 4,352,417 BNT162b2 booster recipients matched with unboosted controls, estimated effectiveness of a booster dose compared with two doses only was 50.7% (95% CI 50.1-51.3) for positive SARS-CoV-2 test, 80.1% (78.3-81.8) for COVID-19 hospitalisation, 88.5% (85.0-91.1) for COVID-19 death, and 80.3% (79.0-81.5) for non-COVID-19 death. Estimated effectiveness was similar among those who had received a BNT162b2 or ChAdOx1-S two-dose primary vaccination course, but effectiveness against severe COVID-19 was slightly lower in those classified as clinically extremely vulnerable (76.3% (73.1-79.1) for COVID-19 hospitalisation, and 85.1% (79.6-89.1) for COVID-19 death). Estimated effectiveness against each outcome was lower in those aged 18-65 years than in those aged 65 and over. Conclusion Our findings are consistent with strong protection of BNT162b2 boosting against positive SARS-CoV-2 test, COVID-19 hospitalisation, and COVID-19 death.

OpenSAFELY NHS Service Restoration Observatory 2: changes in primary care activity across six clinical areas during the COVID-19 pandemic (preprint)

Background The COVID-19 pandemic has disrupted healthcare activity across a broad range of clinical services. The NHS stopped non-urgent work in March 2020, later recommending services be restored to near-normal levels before winter where possible. Aims Using routinely collected data, our aim was to describe changes in the volume and variation of coded clinical activity in general practice in: (i) cardiovascular disease, (ii) diabetes, (iii) mental health, (iv) female and reproductive health, (v) screening, and (vi) processes related to medication. Design and setting With the approval of NHS England, we conducted a cohort study of 23.8 million patient records in general practice, in-situ using OpenSAFELY. Methods We selected common primary care activity using CTV3 codes and keyword searches from January 2019 - December 2020, presenting median and deciles of code usage across practices per month. Results We identified substantial and widespread changes in clinical activity in primary care since the onset of the COVID-19 pandemic, with generally good recovery by December 2020. A few exceptions showed poor recovery and warrant further investigation, such as mental health, e.g. "Depression interim review" (median across practices in December 2020 -41.6% compared to December 2019). Conclusions Granular NHS GP data at population-scale can be used to monitor disruptions to healthcare services and guide the development of mitigation strategies. The authors are now developing real-time monitoring dashboards for key measures identified here as well as further studies, using primary care data to monitor and mitigate the indirect health impacts of Covid-19 on the NHS.

Comparative effectiveness of sotrovimab and molnupiravir for prevention of severe COVID-19 outcomes in non-hospitalised patients: an observational cohort study using the OpenSAFELY platform (preprint)

Objective: To compare the effectiveness of sotrovimab (a neutralising monoclonal antibody) vs. molnupiravir (an antiviral) in preventing severe COVID-19 outcomes in non-hospitalised high-risk COVID-19 adult patients. Design: With the approval of NHS England, we conducted a real-world cohort study using the OpenSAFELY-TPP platform. Setting: Patient-level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on COVID-19 infection and therapeutics, hospital admission and death within the OpenSAFELY-TPP platform, covering a period where both medications were frequently prescribed in community settings. Participants: Non-hospitalised adult COVID-19 patients at high-risk of severe outcomes treated with sotrovimab or molnupiravir between December 16, 2021 and February 10, 2022. Interventions: Sotrovimab or molnupiravir administered in the community by COVID-19 Medicine Delivery Units. Main outcome measure: COVID-19 related hospitalisation or COVID-19 related death within 28 days after treatment initiation. Results: Patients treated with sotrovimab (n=3288) and molnupiravir (n=2663) were similar with respect to most baseline characteristics. The mean age of all 5951 patients was 52 (SD=16) years; 59% were female, 89% White and 87% had three or more COVID-19 vaccinations. Within 28 days after treatment initiation, 84 (1.4%) COVID-19 related hospitalisations/deaths were observed (31 treated with sotrovimab and 53 with molnupiravir). Cox proportional hazards models stratified by area showed that after adjusting for demographics, high-risk cohort categories, vaccination status, calendar time, body mass index and other comorbidities, treatment with sotrovimab was associated with a substantially lower risk than treatment with molnupiravir (hazard ratio, HR=0.53, 95% CI: 0.32-0.88; P=0.014). Consistent results were obtained from propensity score weighted Cox models (HR=0.51, 95% CI: 0.31-0.83; P=0.007) and when restricted to fully vaccinated people (HR=0.52, 95% CI: 0.30-0.90; P=0.020). No substantial effect modifications by other characteristics were detected (all P values for interaction>0.10). Conclusion: In routine care of non-hospitalised high-risk adult patients with COVID-19 in England, those who received sotrovimab were at lower risk of severe COVID-19 outcomes than those receiving molnupiravir.

Changes in English medication safety indicators throughout the COVID-19 pandemic: a federated analysis of 57 million patients' primary care records in situ using OpenSAFELY (preprint)

Objective: To describe the impact of the COVID-19 pandemic on safe prescribing, using the PINCER prescribing indicators; to implement complex prescribing indicators at national scale using GP data. Design: Population based cohort study, with the approval of NHS England using the OpenSAFELY platform. Setting: Electronic health record data from 56.8 million NHS patients' general practice records. Participants: All NHS patients registered at a GP practice using TPP or EMIS computer systems and recorded as at risk of at least one potentially hazardous PINCER indicator between September 2019 and September 2021. Main outcome measure: Monthly trends and between-practice variation for compliance with 13 PINCER measures between September 2019 and September 2021. Results: The indicators were successfully implemented across GP data in OpenSAFELY. Hazardous prescribing remained largely unchanged during the COVID-19 pandemic, with only small reductions in achievement of the PINCER indicators. There were transient delays in blood test monitoring for some medications, particularly ACE inhibitors. All indicators exhibited substantial recovery by September 2021. We identified 1,813,058 patients at risk of at least one hazardous prescribing event. Conclusion: Good performance was maintained during the COVID-19 pandemic across a diverse range of widely evaluated measures of safe prescribing.

Accident and emergency (AE) attendance in England following infection with SARS-CoV-2 Omicron or Delta (preprint)

The SARS-CoV-2 Omicron variant is increasing in prevalence around the world. Accurate estimation of disease severity associated with Omicron is critical for pandemic planning. We found lower risk of accident and emergency (AE) attendance following SARS-CoV-2 infection with Omicron compared to Delta (HR: 0.39 (95% CI: 0.30 - 0.51; P<.0001). For AE attendances that lead to hospital admission, Omicron was associated with an 85% lower hazard compared with Delta (HR: 0.14 (95% CI: 0.09 - 0.24; P<.0001)). Conflicts of InterestsNothing to declare. Funding statementThis work was supported by the Medical Research Council MR/V015737/1. TPP provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. Rosalind Eggo is funded by HDR UK (grant: MR/S003975/1), MRC (grant: MC_PC 19065), NIHR (grant: NIHR200908).

Health care use attributable to COVID-19: A propensity matched national electronic health records cohort study of 249,390 people in Wales, UK. (preprint)

BackgroundTo determine the extent and nature of changes in infected patients healthcare utilization, we studied healthcare contact in the 1-4 weeks and 5-24 weeks following a COVID-19 diagnosis compared to propensity matched controls. MethodsSurvival analysis was used for time to death and first clinical outcomes including clinical terminology concepts for post-viral illness, fatigue, embolism, respiratory conditions, mental and developmental conditions, fit note, or hospital attendance. Increased instantaneous risk for the occurrence of an outcome for positive individuals was quantified using hazard ratios (HR) from Cox Regression and absolute risk was quantified using relative risk (RR) from life table analysis. ResultsCompared to matched individuals testing negative, surviving positive community-tested patients had a higher risk of post-viral illness (HR: 4.57, 95%CI: 1.77-11.80, p=0.002), fatigue (HR: 1.47, 95%CI: 1.24-1.75, p<0.001) and embolism (HR: 1.51, 95%CI: 1.13-2.02, p=0.005) at 5-24 weeks post-diagnosis. In the four weeks after COVID-19 higher rates of sick notes were being issued for community-tested (HR: 3.04, 95%CI: 0.88 to 10.50, p<0.079); the risk was reduced after four weeks, compared to controls. Overall healthcare attendance for anxiety, depression was less likely in those with COVID-19 in the first four weeks (HR: 0.83, 95%CI: 0.73-1.06, p=0.007). After four weeks, anxiety, depression is less likely to occur for the positive community-tested individuals (HR: 0.87, 95%CI: 0.77-1.00, p=0.048), but more likely for positive hospital-tested individuals (HR: 1.16, 95%CI: 1.00-1.45, p=0.053). Although statistical associations between positive infection and post-infection healthcare use are clear, the absolute use of healthcare is very. ConclusionsCommunity COVID-19 disease is associated with increased risks of post-viral illness, fatigue, embolism, depression, anxiety and respiratory conditions. Despite these elevated risks, the absolute healthcare burden is low. Either very small proportions of people experience adverse outcomes following COVID-19 or they are not presenting to healthcare. Trial registrationData held in SAIL databank are anonymised and therefore, no ethical approval is required. All data in SAIL has the permission from the relevant Caldicott Guardian or Data Protection Officer and SAIL-related projects are required to obtain Information Governance Review Panel (IGRP) approval. The IGRP approval number for this study is 1259.