Long-term cardiovascular safety of COVID-19 vaccination according to brand, dose and combinations: Cohort study of 46 million adults in England (preprint)

Using longitudinal health records from 45.7 million adults in England followed for a year, our study compared the incidence of thrombotic and cardiovascular complications after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the first two years of the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA- 1273) These findings support the wide uptake of future COVID-19 vaccination programs.

Risk of cardiovascular events following COVID-19 in people with and without pre-existing chronic respiratory disease (preprint)

Background COVID-19 is associated with a higher risk of cardiovascular outcomes in the general population. People with chronic respiratory disease have a higher risk of cardiovascular disease than the general population therefore, we investigated the association between pre-existing chronic respiratory disease and risk of cardiovascular events following COVID-19 using routinely collected data from 56 million people in England. Methods Primary and secondary care data from the English National Health Service and COVID-19-specific linked data were used to define a population of adults with COVID-19 between 01/01/2020-30/11/2021. Start of follow-up was from first COVID-19 diagnosis. Pre-existing chronic respiratory disease included asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, or pulmonary fibrosis prior to COVID-19 diagnosis. Adjusted Cox Proportional Hazard regression was used to investigate the association between pre-existing chronic respiratory disease and risk of cardiovascular events. Secondary objectives investigated the impact of COVID-19 hospitalisation and vaccine dose on risk of cardiovascular outcomes. Findings A total of 3,670,455 people were included. People with pre-existing respiratory disease had a higher risk of cardiovascular events (adjusted HR 1.11, 95% confidence intervals 1.07-1.14), heart failure (1.15, 1.09-1.21), and pulmonary embolism (1.20, 1.11-1.30) compared with those without pre-existing respiratory disease. Regardless of pre-existing respiratory disease, the risk of cardiovascular events was lower with increasing COVID-19 vaccine dose. Interpretation People with chronic respiratory disease have a higher risk of some cardiovascular outcomes but the risk might be explained by the underlying respiratory condition. Risk of cardiovascular events was lower with increasing COVID-19 vaccine doses regardless of pre-existing chronic respiratory disease. Funding This work was funded by the British Heart Foundation Data Science Centre.

Antipsychotic prescribing and mortality in people with dementia before and during the COVID-19 pandemic: retrospective cohort study (preprint)

Background: Antipsychotic drugs have been associated with increased mortality, stroke and myocardial infarction in people with dementia. Concerns have been raised that antipsychotic prescribing may have increased during the COVID-19 pandemic due to social restrictions imposed to limit the spread of the virus. We used multisource, routinely-collected healthcare data from Wales, UK, to investigate prescribing and mortality trends in people with dementia before and during the COVID-19 pandemic. Methods: We used individual-level, anonymised, population-scale linked health data to identify adults aged >=60 years with a diagnosis of dementia in Wales, UK. We explored antipsychotic prescribing trends over 67 months between 1st January 2016 and 1st August 2021, overall and stratified by age and dementia subtype. We used time series analyses to examine all-cause, myocardial infarction (MI) and stroke mortality over the study period and identified the leading causes of death in people with dementia. Findings: Of 57,396 people with dementia, 11,929 (21%) were prescribed an antipsychotic at any point during follow-up. Accounting for seasonality, antipsychotic prescribing increased during the second half of 2019 and throughout 2020. However, the absolute difference in prescribing rates was small, ranging from 1253 to 1305 per 10,000 person-months. Prescribing in the 60-64 age group and those with Alzheimer's disease increased throughout the 5-year period. All-cause and stroke mortality increased in the second half of 2019 and throughout 2020 but MI mortality declined. From January 2020, COVID-19 was the second commonest underlying cause of death in people with dementia. Interpretation: During the COVID-19 pandemic there was a small increase in antipsychotic prescribing in people with dementia. The long-term increase in antipsychotic prescribing in younger people and in those with Alzheimer's disease warrants further investigation. Funding: British Heart Foundation (BHF) (SP/19/3/34678) via the BHF Data Science Centre led by HDR UK, and the Scottish Neurological Research Fund.

How much did the Covid-19 shielding policy cost in Wales? A Retrospective Cost analysis within the EVITE Immunity study (preprint)

Background: The EVITE Immunity study investigates the effects of shielding Clinically Extremely Vulnerable (CEV) people during the COVID-19 pandemic on health outcomes and healthcare costs in Wales, UK, to help prepare for future pandemics. Shielding was intended to protect those at highest risk of serious harm from COVID-19. We report the cost of implementing shielding in Wales. Methods: The number of people shielding was extracted from the Secure Anonymised Information Linkage Databank. Resources supporting shielding between March and June 2020 were mapped using published reports, web pages, freedom of information requests to Welsh Government and personal communications (e.g. the office of the Chief Medical Officer for Wales). Results: At the beginning of shielding, 117,415 people were on the shielding list. The total additional cost to support those advised to stay home during the initial 14 weeks of the pandemic was £13,307,654 (£113 per person shielded). This included the new resources required to compile the shielding list, inform CEV people of the shielding intervention and provide medicine and food deliveries. The list was adjusted weekly over the 3-month period (130,000 people identified by June 2020) therefore the cost per person shielded lies between £102 and £113. Conclusion: This is the first evaluation of the cost of the measures put in place to support those identified to shield in Wales. However, no data on opportunity cost was available. The true cost of shielding including its budget impact and opportunity costs need to be investigated to decide whether shielding is a worthwhile policy for future health emergencies.

Real-world effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab on preventing hospital admission among higher-risk patients with COVID-19 in Wales: a retrospective cohort study (preprint)

Objective To compare the effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab with no treatment in preventing hospital admission or death in higher-risk patients infected with SARS-CoV-2 in the community. Design Retrospective cohort study of non-hospitalised adult patients with COVID-19 using the Secure Anonymised Information Linkage (SAIL) Databank. Setting A real-world cohort study was conducted within the SAIL Databank (a secure trusted research environment containing anonymised, individual, population-scale electronic health record (EHR) data) for the population of Wales, UK. Participants Adult patients with COVID-19 in the community, at higher risk of hospitalisation and death, testing positive for SARS-CoV-2 between 16th December 2021 and 22nd April 2022. Interventions Molnupiravir, nirmatrelvir-ritonavir, and sotrovimab given in the community by local health boards and the National Antiviral Service in Wales. Main outcome measures All-cause admission to hospital or death within 28 days of a positive test for SARS-CoV-2. Statistical analysis Cox proportional hazard model with treatment status (treated/untreated) as a time-dependent covariate and adjusted for age, sex, number of comorbidities, Welsh Index of Multiple Deprivation, and vaccination status. Secondary subgroup analyses were by treatment type, number of comorbidities, and before and on or after 20th February 2022, when omicron BA.1 and omicron BA.2 were the dominant subvariants in Wales. Results Between 16th December 2021 and 22nd April 2022, 7,103 higher-risk patients were eligible for inclusion in the study. Of these, 2,040 received treatment with molnupiravir (359, 17.6%), nirmatrelvir-ritonavir (602, 29.5%), or sotrovimab (1,079, 52.9%). Patients in the treatment group were younger (mean age 53 vs 57 years), had fewer comorbidities, and a higher proportion had received four or more doses of the COVID-19 vaccine (36.3% vs 17.6%). Within 28 days of a positive test, 628 (9.0%) patients were admitted to hospital or died (84 treated and 544 untreated). The primary analysis indicated a lower risk of hospitalisation or death at any point within 28 days in treated participants compared to those not receiving treatment. The adjusted hazard rate was 35% (95% CI: 18-49%) lower in treated than untreated participants. There was no indication of the superiority of one treatment over another and no evidence of a reduction in risk of hospitalisation or death within 28 days for patients with no or only one comorbidity. In patients treated with sotrovimab, the event rates before and on or after 20th February 2022 were similar (5.0% vs 4.9%) with no significant difference in the hazard ratios for sotrovimab between the time periods. Conclusions In higher-risk adult patients in the community with COVID-19, those who received treatment with molnupiravir, nirmatrelvir-ritonavir, or sotrovimab were at lower risk of hospitalisation or death than those not receiving treatment.

COVID-19 Vaccination in Pregnancy: The Impact of Multimorbidity and Smoking Status on Vaccine Hesitancy, a Cohort Study of 25,111 Women in Wales, UK (preprint)

Abstract Background Multimorbidity and pregnancy are two risk factors for more severe outcomes after a SARS-CoV-2 infection, thus vaccination uptake is important for pregnant women living with multimorbidity. This study aimed to examine the impact of multimorbidity, smoking status, and demographics (age, ethnic group, area of deprivation) on vaccine hesitancy among pregnant women in Wales using electronic health records (EHR) linkage. Methods This cohort study utilised routinely collected, individual-level, anonymised population-scale linked data within the Secure Anonymised Information Linkage (SAIL) Databank. Pregnant women were identified from 13th April 2021 to 31st December 2021. Survival analysis was utilised to examine and compare the length of time to vaccination uptake in pregnancy by multimorbidity and smoking status, as well as depression, diabetes, asthma, and cardiovascular conditions independently. Variation in uptake by; multimorbidity, smoking status, and demographics was examined jointly and separately for the independent conditions using hazard ratios (HR) from the Cox regression model. A bootstrapping internal validation was conducted to assess the performance of the models. Results Within the population cohort, 8,203 (32.7%) received at least one dose of the COVID-19 vaccine during pregnancy, with 8,572 (34.1%) remaining unvaccinated throughout the follow-up period, and 8,336 (33.2%) receiving the vaccine postpartum. Women aged 30 years or older were more likely to have the vaccine in pregnancy. Those who had depression were slightly but significantly more likely to have the vaccine compared to those without depression (HR = 1.08, 95% CI 1.03 to 1.14, p = 0.02). Women living with multimorbidity (> 1 health condition) were 1.12 times more likely to have the vaccine compared to those living without multimorbidity (HR = 1.12, 95% CI 1.04 to 1.19, p = 0.001). Vaccine uptakes were significantly lower among both current smokers and former smokers compared to never smokers (HR = 0.87, 95% CI 0.81 to 0.94, p < 0.001 and HR = 0.92, 95% CI 0.85 to 0.98, p = 0.015 respectively). Uptake was also lower among those living in the most deprived areas compared to those living in the most affluent areas (HR = 0.89, 95% CI 0.83 to 0.96, p = 0.002). The validated model had similar performance and revealed that multimorbidity, smoking status, age, and deprivation level together have a significant impact on vaccine hesitancy (p < 0.05 for all). Conclusion Younger women, living without multimorbidity (zero or only one health condition), current and former smokers, and those living in the more deprived areas are less likely to have the vaccine, thus, a targeted approach to vaccinations may be required for these groups. Women living with multimorbidity are slightly but significantly less likely to be hesitant about COVID-19 vaccination when pregnant.

COVID-19 Vaccination in Pregnancy: The Impact of Multimorbidity and Smoking Status on Vaccine Hesitancy, a Cohort Study of 25,111 Women in Wales, UK (preprint)

Background Multimorbidity and pregnancy are two risk factors for more severe outcomes after a SARS-CoV-2 infection, thus vaccination uptake is important for pregnant women living with multimorbidity. This study aimed to examine the impact of multimorbidity, smoking status, and demographics (age, ethnic group, area of deprivation) on vaccine hesitancy among pregnant women in Wales using electronic health records (EHR) linkage. Methods This cohort study utilised routinely collected, individual-level, anonymised population-scale linked data within the Secure Anonymised Information Linkage (SAIL) Databank. Pregnant women were identified from 13th April 2021 to 31st December 2021. Survival analysis was utilised to examine and compare the length of time to vaccination uptake in pregnancy by multimorbidity and smoking status, as well as depression, diabetes, asthma, and cardiovascular conditions independently. Variation in uptake by; multimorbidity, smoking status, and demographics was examined jointly and separately for the independent conditions using hazard ratios (HR) from the Cox regression model. Results Within the population cohort, 8,203 (32.7%) received at least one dose of the COVID-19 vaccine during pregnancy, with 8,572 (34.1%) remaining unvaccinated throughout the follow-up period, and 8,336 (33.2%) receiving the vaccine postpartum. Women aged 30 years or older were more likely to have the vaccine in pregnancy. Those who had depression were slightly but significantly more likely to have the vaccine compared to those without depression (HR = 1.08, 95% CI 1.03 to 1.14, p = 0.02). Women living with multimorbidity were 1.12 times more likely to have the vaccine compared to those living without multimorbidity (HR = 1.12, 95% CI 1.04 to 1.19, p = 0.001). Vaccine uptakes were significantly lower among both current smokers and former smokers compared to never smokers (HR = 0.87, 95% CI 0.81 to 0.94, p < 0.001 and HR = 0.92, 95% CI 0.85 to 0.98, p = 0.015 respectively). Uptake was also lower among those living in the most deprived areas compared to those living in the most affluent areas (HR = 0.89, 95% CI 0.83 to 0.96, p = 0.002). Conclusion Younger women, living without multimorbidity, current and former smokers, and those living in the more deprived areas are less likely to have the vaccine, thus, a targeted approach to vaccinations may be required for these groups. Women living with multimorbidity are slightly but significantly less likely to be hesitant about COVID-19 vaccination when pregnant.

Developing a research ready population-scale linked data ethnicity-spine in Wales (preprint)

Introduction: Ethnicity information is recorded routinely in electronic health records (EHRs); however, to date, there is no national standard or framework for harmonisation of the existing records. Methods and analysis The national ethnicity-spine uses anonymised individual-level population-scale ethnicity data from 26 EHR available through the Secure Anonymised Information Linkage (SAIL) Databank. A total of 46 million ethnicity records for 4,297,694 individuals in Wales-UK over 22 years (between 2000 and 2021) have been compiled in a harmonised, deduplicated longitudinal research ready data asset. We serialised this data and compared distribution of records over time for four selection approaches (Latest, Mode, Weighted-Mode and Composite) across age bands, sex, deprivation quintiles, health board, and residential location, against the ONS census 2011. The distribution of the dominant group (White) is minimally affected based on the four different selection approaches. Across all other ethnicity categorisations, the Mixed group was most susceptible to variation in distribution depending on the selection approach used and varied from a 0.6% prevalence across the Latest and Mode approach to a 1.1% prevalence for the Weighted-Mode, compared to the 3.1% prevalence for the Composite approach. Substantial alignment was observed with ONS census with the Latest group method (kappa= 0.68, 95% CI [0.67,0.71]) across all sub-groups. Conclusion We provides a reproducible EHR based resource enabling the investigation and evaluation of health inequalities related to ethnic groups in Wales. This generalisable method informs opportunities for the transferability of this methodology across the UK to platforms with comparable routine data sources. Ethics and dissemination This work was supported by the Con-COV team funded by Medical Research Council, Health Data Research UK, ADR Wales funded by ADR UK through the Economic and Social Research Council, and the Wales COVID-19 Evidence Centre, funded by Health and Care Research Wales.

Digital ethnicity data in population-wide electronic health records in England: a description of completeness, coverage, and granularity of diversity (preprint)

Background The link between ethnicity and healthcare inequity, and the urgency for better data is well-recognised. This study describes ethnicity data in nation-wide electronic health records in England, UK. Methods We conducted a retrospective cohort study using de-identified person-level records for the England population available in the National Health Service (NHS) Digital trusted research environment. Primary care records (GDPPR) were linked to hospital and national mortality records. We assessed completeness, consistency, and granularity of ethnicity records using all available SNOMED-CT concepts for ethnicity and NHS ethnicity categories. Findings From 61.8 million individuals registered with a primary care practice in England, 51.5 (83.3%) had at least one ethnicity record in GDPPR, increasing to 93·9% when linked with hospital records. Approximately 12·0% had at least two conflicting ethnicity codes in primary care records. Women were more likely to have ethnicity recorded than men. Ethnicity was missing most frequently in individuals from 18 to 39 years old and in the southern regions of England. Individuals with an ethnicity record had more comorbidities recorded than those without. Of 489 SNOMED-CT ethnicity concepts available, 255 were used in primary care records. Discrepancies between SNOMED-CT and NHS ethnicity categories were observed, specifically within “Other-” ethnicity groups. Interpretation More than 250 ethnicity sub-groups may be found in health records for the English population, although commonly categorised into “White”, “Black”, “Asian”, “Mixed”, and “Other”. One in ten individuals do not have ethnicity information recorded in primary care or hospital records. SNOMED-CT codes represent more diversity in ethnicity groups than the NHS ethnicity classification. Improved recording of self-reported ethnicity at first point-of-care and consistency in ethnicity classification across healthcare settings can potentially improve the accuracy of ethnicity in research and ultimately care for all ethnicities. Funding British Heart Foundation Data Science Centre led by Health Data Research UK. Research in context Evidence before this study Ethnicity has been highlighted as a significant factor in the disproportionate impact of SARS-CoV-2 infection and mortality. Better knowledge of ethnicity data recorded in real clinical practice is required to improve health research and ultimately healthcare. We searched PubMed from database inception to 14 th July 2022 for publications using the search terms “ethnicity” and “electronic health records” or “EHR,” without language restrictions. 228 publications in 2019, before the COVID-19 pandemic, and 304 publications between 2020 and 2022 were identified. However, none of these publications used or reported any of over 400 available SNOMED-CT concepts for ethnicity to account for more granularity and diversity than captured by traditional high-level classification limited to 5 to 9 ethnicity groups. Added value of this study We provide a comprehensive study of the largest collection of ethnicity records from a national-level electronic health records trusted research environment, exploring completeness, consistency, and granularity. This work can serve as a data resource profile of ethnicity from routinely-collected EHR in England. Implications of all the available evidence To achieve equity in healthcare, we need to understand the differences between individuals, as well as the influence of ethnicity both on health status and on health interventions, including variation in the behaviour of tests and therapies. Thus, there is a need for measurements, thresholds, and risk estimates to be tailored to different ethnic groups. This study presents the different medical concepts describing ethnicity in routinely collected data that are readily available to researchers and highlights key elements for improving their accuracy in research. We aim to encourage researchers to use more granular ethnicity than the than typical approaches which aggregate ethnicity into a limited number of categories, failing to reflect the diversity of underlying populations. Accurate ethnicity data will lead to a better understanding of individual diversity, which will help to address disparities and influence policy recommendations that can translate into better, fairer health for all.

Indirect effects of the first two years of the COVID-19 pandemic on secondary care for cardiovascular disease in the UK: an electronic health record analysis across three countries. (preprint)

BackgroundAlthough morbidity and mortality from COVID-19 have been widely reported, the indirect effects of the pandemic beyond 2020 on other major diseases and health service activity have not been well described. MethodsAnalyses used national administrative electronic hospital records in England, Scotland and Wales for 2016-2021. Admissions and procedures during the pandemic (2020-2021) related to six major cardiovascular conditions (acute coronary syndrome, heart failure, stroke/transient ischaemic attack, peripheral arterial disease, aortic aneurysm, and venous thromboembolism) were compared to the annual average in the pre-pandemic period (2016-2019). Differences were assessed by time period and urgency of care. ResultsIn 2020, there were 31,064 (-6%) fewer hospital admissions (14,506 [-4%] fewer emergencies, 16,560 [-23%] fewer elective admissions) compared to 2016-2019 for the six major cardiovascular diseases combined. The proportional reduction in admissions was similar in all three countries. Overall, hospital admissions returned to pre-pandemic levels in 2021. Elective admissions remained substantially below expected levels for almost all conditions in all three countries (-10,996 [-15%] fewer admissions). However, these reductions were offset by higher than expected total emergency admissions (+25,878 [+6%] higher admissions), notably for heart failure and stroke in England, and for venous thromboembolism in all three countries. Analyses for procedures showed similar temporal variations to admissions. ConclusionThis study highlights increasing emergency cardiovascular admissions as a result of the pandemic, in the context of a substantial and sustained reduction in elective admissions and procedures. This is likely to increase further the demands on cardiovascular services over the coming years. Key QuestionWhat is the impact in 2020 and 2021 of the COVID-19 pandemic on hospital admissions and procedures for six major cardiovascular diseases in England, Scotland and Wales? Key FindingIn 2020, there were 6% fewer hospital admissions (emergency: -4%, elective: -23%) compared to 2016-2019 for six major cardiovascular diseases, across three UK countries. Overall, admissions returned to pre-pandemic levels in 2021, but elective admissions remained below expected levels. Take-home MessageThere was increasing emergency cardiovascular admissions as a result of the pandemic, with substantial and sustained reduction in elective admissions and procedures. This is likely to increase further the demands on cardiovascular services over the coming years.

Vaccine effectiveness for preventing COVID-19 hospital admission during pregnancy: a population-based cohort study in England during the Alpha and Delta waves of the SARS-CoV-2 pandemic (preprint)

Objective: To estimate vaccine effectiveness (VE) for preventing COVID-19 hospital admission in women first infected with SARS-CoV-2 during pregnancy, and assess how this compares to VE among women of reproductive age who were not pregnant when first infected. Design: Population-based cohort study using national, linked Census and administrative data. Setting: England, United Kingdom, from 8th December 2020 to 31st August 2021. Participants: 815,4777 women aged 18 to 45 years (mean age, 30.4 years) who had documented evidence of a first SARS-CoV-2 infection in NHS Test and Trace data or Hospital Episode Statistics. Main outcome measures: A hospital inpatient episode where COVID-19 was recorded as the primary diagnosis. Cox proportional hazards models, adjusted for calendar time of infection and sociodemographic factors related to vaccine uptake and risk of severe COVID-19, were used to estimate VE as the complement of the hazard ratio for COVID-19 hospital admission. Results: Compared with unvaccinated pregnant women, the adjusted rate of COVID-19 hospital admission was 76% (95% confidence interval 69% to 82%) lower for single-vaccinated pregnant women and 83% (75% to 88%) lower for double-vaccinated pregnant women. These estimates were similar to those found for non-pregnant women: 79% (76% to 81%) for single-vaccinated and 82% (80% to 83%) for double-vaccinated. Among those vaccinated more than 90 days before infection, being double-vaccinated was associated with a greater reduction in risk than being single-vaccinated. Conclusions: COVID-19 vaccination is associated with reduced rates of severe illness in pregnant women infected with SARS-CoV-2, and the reduction in risk is similar to that for non-pregnant women. Waning of vaccine effectiveness occurs more quickly after one dose of a vaccine than two doses.

Harmonising electronic health records for reproducible research: challenges, solutions and recommendations from a UK-wide COVID-19 research collaboration (preprint)

Background The CVD-COVID-UK consortium was formed to understand the relationship between COVID-19 and cardiovascular diseases through analyses of harmonised electronic health records (EHRs) across the four UK nations. Beyond COVID-19, data harmonisation and common approaches enables analysis within and across independent Trusted Research Environments. Here we describe the reproducible harmonisation method developed using large-scale EHRs in Wales to accommodate the fast and efficient implementation of cross-nation analysis in England and Wales as part of the CVD-COVID-UK programme. We characterise current challenges and share lessons learnt.Methods Serving the scope and scalability of multiple study protocols, we used linked, anonymised individual-level EHR, demographic and administrative data held within the SAIL Databank for the population of Wales. The harmonisation method was implemented as a four-layer reproducible process, starting from raw data in the first layer. Then each of the layers two to four is framed by, but not limited to, the characterised challenges and lessons learnt. We achieved curated data as part of our second layer, followed by extracting phenotyped data in the third layer. We captured any project-specific requirements in the fourth layer.Results Using the implemented four-layer harmonisation method, we retrieved approximately 100 health-related variables for the 3.2 million individuals in Wales, which are harmonised with corresponding variables for > 56 million individuals in England. We processed 13 data sources into the first layer of our harmonisation method: five of these are updated daily or weekly, and the rest at various frequencies providing sufficient data flow updates for frequent capturing of up-to-date demographic, administrative and clinical information.Conclusions We implemented an efficient, transparent, scalable, and reproducible harmonisation method that enables multi-nation collaborative research. With a current focus on COVID-19 and its relationship with cardiovascular outcomes, the harmonised data has supported a wide range of research activities across the UK.

Inequalities in colorectal cancer screening uptake in Wales: an examination of the impact of the temporary suspension of the screening programme during the COVID-19 pandemic (preprint)

Background Response to the early stages of the COVID-19 pandemic resulted in the temporary disruption of cancer screening in the UK, and strong public messaging to stay safe and to protect NHS capacity. Following reintroduction in services, we explored the impact on inequalities in uptake of the Bowel Screening Wales (BSW) programme to identify groups who may benefit from tailored interventions. Methods Records within the BSW were linked to electronic health records (EHR) and administrative data within the Secured Anonymised Information Linkage (SAIL) Databank. Ethnic group was obtained from a linked data method available within SAIL. We examined uptake for the first 3 months of invitations (August to October) following the reintroduction of BSW programme in 2020, compared to the same period in the preceding 3 years. Uptake was measured across a 6 month follow-up period. Logistic models were conducted to analyse variations in uptake by sex, age group, income deprivation quintile, urban/rural location, ethnic group, and clinically extremely vulnerable (CEV) status in each period; and to compare uptake within sociodemographic groups between different periods. Results Uptake during August to October 2020 (period 2020/21; 60.4%) declined compared to the same period in 2019/20 (62.7%) but remained above the 60% Welsh standard. Variation by sex, age, income deprivation, and ethnic groups was observed in all periods studied. Compared to the pre-pandemic period in 2019/20, uptake declined for most demographic groups, except for older individuals (70-74 years) and those in the most income deprived group. Uptake continues to be lower in males, younger individuals, people living in the most income deprived areas and those of Asian and unknown ethnic backgrounds. Conclusions Our findings are encouraging with overall uptake achieving the 60% Welsh standard during the first three months after the programme restarted in 2020 despite the disruption. Inequalities did not worsen after the programme resumed activities but variations in CRC screening in Wales associated with sex, age, deprivation and ethnicity remain. This needs to be considered in targeting strategies to improve uptake and informed choice in CRC screening to avoid exacerbating disparities in CRC outcomes as screening services recover from the pandemic.

COVID-19 vaccination in pregnancy: views and vaccination uptake rates in pregnancy, a mixed methods analysis from the Born In Wales study (preprint)

Background Vaccine hesitancy amongst pregnant women has been found to be a concern during past epidemics. This study aimed to 1) estimate COVID-19 vaccination rates among pregnant women in Wales and their association with age, ethnicity, and area of deprivation, using electronic health records (EHR) linkage, and 2) explore pregnant women’s views on receiving the COVID-19 vaccine during pregnancy using data from a survey recruiting via social media (Facebook, Twitter), through midwives, and posters in hospitals (Born in Wales Cohort).Methods This was a mixed-methods study utilising routinely collected linked data from the Secure Anonymised Information Linkage (SAIL) (Objective 1) and the Born-In-Wales Birth Cohort participants (Objective 2). Survival analysis was utilised to examine and compare the length of time to vaccination uptake in pregnancy, and variation in uptake by; age, ethnicity, and deprivation area was examined using hazard ratios (HR) from Cox regression. Codebook thematic analysis was used to generate themes from an open-ended question on the survey.Results Population-level data linkage (objective 1): Within the population cohort, 32.7% (n = 8,203) were vaccinated (at least one dose of the vaccine) during pregnancy, 34.1% (n = 8,572) remained unvaccinated throughout follow-up period, and 33.2% (n = 8,336) received the vaccine postpartum. Younger women (< 30 years) were less likely to have the vaccine and those living in areas of high deprivation were also less likely to have the vaccine (HR = 0.88, 95% CI 0.82 to 0.95). Asian and other ethnic groups were 1.12 and 1.18 times more likely to have the vaccine in pregnancy compared to women of White ethnicity (HR = 1.12, 95% CI 1.00 to 1.25) and (HR = 1.18, 95% CI 1.03 to 1.37) respectively. Survey responses (objective 2): 69% of participants stated that they would be happy to have the vaccine during pregnancy (n = 207). The remainder, 31%, indicated that they would not have the vaccine during pregnancy (n = 94). Reasons for having the vaccine included protecting self and baby, perceived risk level, and receipt of sufficient evidence and advice. Reasons for vaccine refusal included lack of research about long-term outcomes for the baby, anxiety about vaccines, inconsistent advice/information, and preference to wait until after the pregnancy.Conclusion Potentially only 1 in 3 pregnant women would have the COVID-19 vaccine during pregnancy, even though 2 in 3 reported they would have the vaccination, thus it is critical to develop tailored strategies to increase its acceptance rate and to decrease vaccine hesitancy. A targeted approach to vaccinations may be required for groups such as younger people and those living in higher deprivation level areas.

Temporal sequencing in multimorbidity using population-scale linked data for 1.7 million individuals with 20-year follow-up (preprint)

Multimorbidity is defined as the coexistence of two or more chronic health conditions in an individual. The objective of this study was to examine how diseases in a cluster of physical-mental health multimorbidity with a high all-cause mortality (psychosis, diabetes, and congestive heart failure) develop and coexist over time, and to assess the associated impact of different temporal sequences on mortality. Population-scale, individual-level, anonymised, linked, demographic, administrative and electronic health record data were modelled using multi-state models for 1,675,585 individuals over a 20-year period (2000–2019). Cox regression models were used to estimate baseline hazards for transitions between states, adjusted for gender, age, and area-level deprivation. Our findings suggest that the order of disease acquisition in physical-mental health multimorbidity had an important impact and complex relationship on patient mortality. Individuals developing diabetes, psychosis, and congestive heart failure, in that order, had an increased all-cause mortality rate compared to the development of the same conditions in a different order, resulting in the highest loss in expectation of life of 13 years at age 50 compared to the general population. Congestive heart failure as a single condition and in combination with psychosis had an equally high loss in expectation of life. Identification and therapeutic targets for psychosis and congestive heart failure may be beneficial within 5 years following an initial diagnosis of diabetes. The use of multi-state models offers a flexible framework to assess temporal sequences of diseases and associated patient outcomes, and allows identification of potential risk factors, screening opportunities, and therapeutic targets in multimorbidity.

Risk of myocarditis and pericarditis following COVID-19 vaccination in England and Wales (preprint)

We describe our analyses of data from over 52 million people in England and Wales, representing near-complete coverage of the relevant population, to assess the risk of myocarditis and pericarditis following COVID-19 vaccination. A self-controlled case series (SCCS) design has previously reported increased risk of myocarditis after first doses of ChAdOx1, BNT162b2, and mRNA-1273 vaccinations and after second doses of the mRNA COVID-19 vaccinations in England. Here, we use a cohort design to estimate hazard ratios for hospitalised or fatal myocarditis/pericarditis and excess events after first and second doses of BNT162b2 and ChAdOx1 vaccinations. SCCS and cohort designs are subject to different assumptions and biases and therefore provide the opportunity for triangulation of evidence. In contrast to the findings from the SCCS approach previously reported for England, we found evidence of lower incidence of hospitalised or fatal myocarditis/pericarditis after first dose ChAdOx1 and BNT162b2 vaccination.

Pre-COVID-19 pandemic health-related behaviours in children (2018-2020) and association with being tested for SARS-CoV-2 and testing positive for SARS-CoV-2 (2020-2021): a retrospective cohort study using survey data linked with routine health data in Wales, UK (preprint)

ABSTRACT Objectives Examine if pre-COVID-19 pandemic (prior March 2020) health-related behaviours during primary school are associated with i) being tested for SARS-CoV-2 and ii) testing positive between 1 March 2020 to 31 August 2021. Design Retrospective cohort study using an online cohort survey (January 2018 to February 2020) linked to routine PCR SARS-CoV-2 test results. Setting Children attending primary schools in Wales (2018-2020), UK who were part of the HAPPEN school network. Participants Complete linked records of eligible participants were obtained for n=7,062 individuals. 39.1% (n=2,764) were tested (age 10.6±0.9, 48.9% girls) and 8.1% (n=569) tested positive for SARS-CoV-2 (age 10.6±1.0, 54.5% girls). Main outcome measures Logistic regression of health-related behaviours and demographics were used to determine Odds Ratios (OR) of factors associated with i) being tested for SARS-CoV-2 and ii) testing positive for SARS-CoV-2. Results Consuming sugary snacks (1-2 days/week OR=1.24, 95% CI 1.04 – 1.49; 5-6 days/week 1.31, 1.07 – 1.61; reference 0 days) can swim 25m (1.21, 1.06 – 1.39) and age (1.25, 1.16 – 1.35) were associated with an increased likelihood of being tested for SARS-CoV-2. Eating breakfast (1.52, 1.01 – 2.27), weekly physical activity ≥ 60 mins (1-2 days 1.69, 1.04 – 2.74; 3-4 days 1.76, 1.10 – 2.82, reference 0 days), out of school club participation (1.06, 1.02 – 1.10), can ride a bike (1.39, 1.00 – 1.93), age (1.16, 1.05 – 1.28) and girls (1.21, 1.00 – 1.46) were associated with an increased likelihood of testing positive for SARS-CoV-2. Living in least deprived quintiles 4 (0.64, 0.46 – 0.90) and 5 (0.64, 0.46 – 0.89) compared to the most deprived quintile was associated with a decreased likelihood. Conclusions Associations may be related to parental health literacy and monitoring behaviours. Physically active behaviours may include co-participation with others, and exposure to SARS-CoV-2. A risk versus benefit approach must be considered given the importance of health-related behaviours for development. STRENGTHS AND LIMITATIONS Investigation of the association of pre-pandemic child health-related behaviour measures with subsequent SARS-CoV-2 testing and infection. Reporting of multiple child health behaviours linked at an individual-level to routine records of SARS-CoV-2 testing data through the SAIL Databank. Child-reported health behaviours were measured before the COVID-19 pandemic (1 January 2018 to 28 February 2020) which may not reflect behaviours during COVID-19. Health behaviours captured through the national-scale HAPPEN survey represent children attending schools that engaged with the HAPPEN Wales primary school network and may not be representative of the whole population of Wales. The period of study for PCR-testing for and testing positive for SARS-CoV-2 includes a time frame with varying prevalence rates, approaches to testing children (targeted and mass testing) and restrictions which were not measured in this study.

The adverse impact of COVID-19 pandemic on cardiovascular disease prevention and management in England, Scotland and Wales: A population-scale descriptive analysis of trends in medication data (preprint)

Objectives: To estimate the impact of the COVID-19 pandemic on cardiovascular disease (CVD) and CVD management using routinely collected medication data as a proxy. Design: Descriptive and interrupted time series analysis using anonymised individual-level population-scale data for 1.32 billion records of dispensed CVD medications across 15.8 million individuals in England, Scotland and Wales. Setting: Community dispensed CVD medications with 100% coverage from England, Scotland and Wales, plus primary care prescribed CVD medications from England (including 98% English general practices). Participants: 15.8 million individuals aged 18+ years alive on 1st April 2018 dispensed at least one CVD medicine in a year from England, Scotland and Wales. Main outcome measures: Monthly counts, percent annual change (1st April 2018 to 31st July 2021) and annual rates (1st March 2018 to 28th February 2021) of medicines dispensed by CVD/ CVD risk factor; prevalent and incident use. Results: Year-on-year change in dispensed CVD medicines by month were observed, with notable uplifts ahead of the first (11.8% higher in March 2020) but not subsequent national lockdowns. Using hypertension as one example of the indirect impact of the pandemic, we observed 491,203 fewer individuals initiated antihypertensive treatment across England, Scotland and Wales during the period March 2020 to end May 2021 than would have been expected compared to 2019. We estimated that this missed antihypertension treatment could result in 13,659 additional CVD events should individuals remain untreated, including 2,281 additional myocardial infarctions (MIs) and 3,474 additional strokes. Incident use of lipid-lowering medicines decreased by an average 14,793 per month in early 2021 compared with the equivalent months prior to the pandemic in 2019. In contrast, the use of incident medicines to treat type-2 diabetes (T2DM) increased by approximately 1,642 patients per month. Conclusions: Management of key CVD risk factors as proxied by incident use of CVD medicines has not returned to pre-pandemic levels in the UK. Novel methods to identify and treat individuals who have missed treatment are urgently required to avoid large numbers of additional future CVD events, further adding indirect cost of the COVID-19 pandemic.

Association of COVID-19 with arterial and venous vascular diseases: a population-wide cohort study of 48 million adults in England and Wales (preprint)

Importance: The long-term effects of COVID-19 on the incidence of vascular diseases are unclear. Objective: To quantify the association between time since diagnosis of COVID-19 and vascular disease, overall and by age, sex, ethnicity, and pre-existing disease. Design: Cohort study based on population-wide linked electronic health records, with follow up from January 1st to December 7th 2020. Setting and participants: Adults registered with an NHS general practice in England or Wales and alive on January 1st 2020. Exposures: Time since diagnosis of COVID-19 (categorised as 0-6 days, 1-2 weeks, 3-4, 5-8, 9-12, 13-26 and 27-49 weeks since diagnosis), with and without hospitalisation within 28 days of diagnosis. Main outcomes and measures: Primary outcomes were arterial thromboses (mainly acute myocardial infarction and ischaemic stroke) and venous thromboembolic events (VTE, mainly pulmonary embolism and lower limb deep vein thrombosis). We also studied other vascular events (transient ischaemic attack, haemorrhagic stroke, heart failure and angina). Hazard ratios were adjusted for demographic characteristics, previous disease diagnoses, comorbidities and medications. Results: Among 48 million adults, 130,930 were and 1,315,471 were not hospitalised within 28 days of COVID-19. In England, there were 259,742 first arterial thromboses and 60,066 first VTE during 41.6 million person-years follow-up. Adjusted hazard ratios (aHRs) for first arterial thrombosis compared with no COVID-19 declined rapidly from 21.7 (95% CI 21.0-22.4) to 3.87 (3.58-4.19) in weeks 1 and 2 after COVID-19, 2.80 (2.61-3.01) during weeks 3-4 then to 1.34 (1.21-1.48) during weeks 27-49. aHRs for first VTE declined from 33.2 (31.3-35.2) and 8.52 (7.59-9.58) in weeks 1 and 2 to 7.95 (7.28-8.68) and 4.26 (3.86-4.69) during weeks 3-4 and 5-8, then 2.20 (1.99-2.44) and 1.80 (1.50-2.17) during weeks 13-26 and 27-49 respectively. aHRs were higher, for longer after diagnosis, after hospitalised than non-hospitalised COVID-19. aHRs were also higher among people of Black and Asian than White ethnicity and among people without than with a previous event. Across the whole population estimated increases in risk of arterial thromboses and VTEs were 2.5% and 0.6% respectively 49 weeks after COVID-19, corresponding to 7,197 and 3,517 additional events respectively after 1.4 million COVID-19 diagnoses. Conclusions and Relevance: High rates of vascular disease early after COVID-19 diagnosis decline more rapidly for arterial thromboses than VTEs but rates remain elevated up to 49 weeks after COVID-19. These results support continued policies to avoid COVID-19 infection with effective COVID-19 vaccines and use of secondary preventive agents in high-risk patients.