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.

Impact of COVID-19 on mental illness in vaccinated and unvaccinated people: a population-based cohort study in OpenSAFELY (preprint)

Background: COVID-19 is associated with subsequent mental illness in both hospital- and population-based studies. Evidence regarding effects of COVID-19 vaccination on mental health consequences of COVID-19 is limited. Methods: With the approval of NHS England, we used linked electronic health records (OpenSAFELY-TPP) to conduct analyses in a 'pre-vaccination' cohort (17,619,987 people) followed during the wild-type/Alpha variant eras (January 2020-June 2021), and 'vaccinated' and 'unvaccinated' cohorts (13,716,225 and 3,130,581 people respectively) during the Delta variant era (June-December 2021). We estimated adjusted hazard ratios (aHRs) comparing the incidence of mental illness after diagnosis of COVID-19 with the incidence before or without COVID-19. Outcomes: We considered eight outcomes: depression, serious mental illness, general anxiety, post-traumatic stress disorder, eating disorders, addiction, self-harm, and suicide. Incidence of most outcomes was elevated during weeks 1-4 after COVID-19 diagnosis, compared with before or without COVID-19, in each cohort. Vaccination mitigated the adverse effects of COVID-19 on mental health: aHRs (95% CIs) for depression and for serious mental illness during weeks 1-4 after COVID-19 were 1.93 (1.88-1.98) and 1.42 (1.24-1.61) respectively in the pre-vaccination cohort and 1.79 (1.68-1.91) and 2.21 (1.99-2.45) respectively in the unvaccinated cohort, compared with 1.16 (1.12-1.20) and 0.91 (0.84-0.98) respectively in the vaccinated cohort. Elevation in incidence was higher, and persisted for longer, after hospitalised than non-hospitalised COVID-19. Interpretation: Incidence of mental illness is elevated for up to a year following severe COVID-19 in unvaccinated people. Vaccination mitigates the adverse effect of COVID-19 on mental health. Funding: Medical Research Council (MC_PC_20059) and NIHR (COV-LT-0009).

Diabetes following SARS-CoV-2 infection: Incidence, persistence, and implications of COVID-19 vaccination. A cohort study of fifteen million people. (preprint)

Background Type 2 diabetes (T2DM) incidence is increased after diagnosis of COVID-19. The impact of vaccination on this increase, for how long it persists, and the effect of COVID-19 on other types of diabetes remain unclear. Methods With NHS England approval, we studied diabetes incidence following COVID-19 diagnosis in pre-vaccination (N=15,211,471, January 2020-December 2021), vaccinated (N =11,822,640), and unvaccinated (N=2,851,183) cohorts (June-December 2021), using linked electronic health records. We estimated adjusted hazard ratios (aHRs) comparing diabetes incidence post-COVID-19 diagnosis with incidence before or without diagnosis up to 102 weeks post-diagnosis. Results were stratified by COVID-19 severity (hospitalised/non-hospitalised) and diabetes type. Findings In the pre-vaccination cohort, aHRS for T2DM incidence after COVID-19 (compared to before or without diagnosis) declined from 3.01 (95% CI: 2.76,3.28) in weeks 1-4 to 1.24 (1.12,1.38) in weeks 53-102. aHRS were higher in unvaccinated than vaccinated people (4.86 (3.69,6.41)) versus 1.42 (1.24,1.62) in weeks 1-4) and for hospitalised COVID-19 (pre-vaccination cohort 21.1 (18.8,23.7) in weeks 1-4 declining to 2.04 (1.65,2.51) in weeks 52-102), than non-hospitalised COVID-19 (1.45 (1.27,1.64) in weeks 1-4, 1.10 (0.98,1.23) in weeks 52-102). T2DM persisted for 4 months after COVID-19 for ~73% of those diagnosed. Patterns were similar for Type 1 diabetes, though excess incidence did not persist beyond a year post-COVID-19. Interpretation Elevated T2DM incidence after COVID-19 is greater, and persists longer, in hospitalised than non-hospitalised people. It is markedly less apparent post-vaccination. Testing for T2DM after severe COVID-19 and promotion of vaccination are important tools in addressing this public health problem.

The Cost of Keeping Patients Waiting: Retrospective Treatment-Control Study of Additional Healthcare Utilisation for UK Patients Awaiting Elective Treatment Following COVID-19 (preprint)

ObjectiveThe COVID-19 pandemic has led to increased waiting times for elective treatments in many countries. This study seeks to address a deficit in the literature concerning the effect of long waits on the wider consumption of healthcare resources. MethodsWe carried out a retrospective treatment-control study in a healthcare system in South West England from 15 June 2021 to 15 December 2021. We compared weekly contacts with health services of patients waiting over 18 weeks for treatment ( Treatments) and people not on a waiting list ( Controls). Controls were matched to Treatments based on age, sex, deprivation and multimorbidity. Treatments were stratified by the clinical specialty of the awaited treatment, with healthcare usage assessed over various healthcare settings. T-tests assessed whether there was an increase in healthcare utilisation and bootstrap resampling was used to estimate the magnitude of any differences. ResultsA total of 44,616 patients were waiting over 18 weeks (the constitutional target in England) for treatment during the study period. Evidence suggests increases (p < 0.05) in healthcare utilisation for all specialties. Patients in the Cardiothoracic Surgery specialty had the largest increase, requiring 17.9 [4.3, 33.8] additional contacts with secondary care and 17.3 [-1.1, 34.1] additional prescriptions per year. ConclusionPeople waiting for treatment consume higher levels of healthcare than comparable individuals not on a waiting list. These findings are relevant for clinicians and managers in better understanding patient need and reducing harm. Results also highlight the possible false economy in failing to promptly resolve long elective waits. HighlightsO_LILong waits for elective care can result in additional healthcare needs to manage symptoms up to the point of definitive treatment. While previous studies indicate some association, these mainly consider only a single elective specialty and are limited in the range of healthcare settings covered. C_LIO_LIThe large number of long-wait pathways produced as a consequence of COVID-19 disruption allows for a more holistic analysis, covering the full range of elective treatment specialties and wider healthcare impacts across primary, secondary, mental health, and community care, as well as emergency service calls and prescriptions. C_LIO_LIAnalysis of 44,616 elective care pathways reveals evidence of increases in wider healthcare consumption additional to that expected for similar patients not awaiting elective treatment. This suggests a false economy in failing to promptly resolve elective pathways, which should be reflected by healthcare providers in long-term resource allocation decisions. C_LI

Can computer simulation support strategic service planning? Modelling a large integrated mental health system on recovery from COVID-19 (preprint)

Background COVID-19 has had a significant impact on people's mental health and mental health services. During the first year of the pandemic, existing demand was not fully met while new demand was generated, resulting in large numbers of people requiring support. To support mental health services to recover without being overwhelmed, it was important to know where services will experience increased pressure, and what strategies could be implemented to mitigate this. Methods We implemented a computer simulation model of patient flow through an integrated mental health service in Southwest England covering General Practice (GP), community-based - talking therapies - (IAPT), acute hospital care, and specialist care settings. The model was calibrated on data from 1 April 2019 to 1 April 2021. Model parameters included patient demand, service-level length of stay, and probabilities of transitioning to other care settings. We used the model to compare - do nothing - (baseline) scenarios to - what if -(mitigation) scenarios, including increasing capacity and reducing length of stay, for two future demand trajectories from 1 April 2021 onwards. Results The results from the simulation model suggest that, without mitigation, the impact of COVID-19 will be an increase in pressure on GP and specialist community based services by 50% and 50-100% respectively. Simulating the impact of possible mitigation strategies, results show that increasing capacity in lower-acuity services, such as GP, results in demand being shifted to other parts of the mental health system while decreasing length of stay in higher acuity services is insufficient to mitigate the impact of increased demand. Conclusion In capturing the interrelation of patient flow related dynamics between various mental health care settings, we demonstrate the value of computer simulation for assessing the impact of interventions on system flow.

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.

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.

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.

Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, and thrombocytopenic events: whole population cohort study in 46 million adults in England (preprint)

BackgroundThromboses in unusual locations after the COVID-19 vaccine ChAdOx1-S have been reported. Better understanding of population-level thrombotic risks after COVID-19 vaccination is needed. MethodsWe analysed linked electronic health records from adults living in England, from 8th December 2020 to 18th March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous and thrombocytopenic outcomes 1-28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and [≥]70 years, and adjusted for age, sex, comorbidities, and social and demographic factors. ResultsOf 46,162,942 adults, 21,193,814 (46%) had their first vaccination during follow-up. Adjusted HRs 1-28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and [≥]70 respectively, were 0.97 (95% CI: 0.90-1.05) and 0.58 (0.53-0.63) for venous thromboses, and 0.90 (0.86-0.95) and 0.76 (0.73-0.79) for arterial thromboses. Corresponding HRs for BNT162b2 were 0.81 (0.74-0.88) and 0.57 (0.53-0.62) for venous thromboses, and 0.94 (0.90-0.99) and 0.72 (0.70-0.75) for arterial thromboses. HRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines. Rates of intracranial venous thrombosis (ICVT) and thrombocytopenia in adults aged <70 years were higher 1-28 days after ChAdOx1-S (adjusted HRs 2.27, 95% CI:1.33- 3.88 and 1.71, 1.35-2.16 respectively), but not after BNT162b2 (0.59, 0.24-1.45 and 1.00, 0.75-1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1-28 days after ChAdOx1-S were 0.9-3 per million, varying by age and sex. ConclusionsIncreases in ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults <40 years are needed. For people aged [≥]70 years, rates of arterial or venous thrombotic, events were generally lower after either vaccine.

Maintaining face-to-face contact during the COVID-19 pandemic: a longitudinal qualitative investigation in UK primary care (preprint)

BackgroundIn March 2020 the COVID-19 pandemic required a rapid reconfiguration of UK general practice to minimise face-to-face contact with patients to reduce infection risk. However, some face-to-face contact remained necessary and practices needed to ensure such contact could continue safely.AimTo examine how practices determined when face-to-face contact was necessary and how face-to-face consultations were reconfigured to reduce COVID-19 infection risk. Design and SettingQualitative interview study in general practices in Bristol, North Somerset and South Gloucestershire.MethodLongitudinal semi-structured interviews with clinical and managerial practice staff at four timepoints between May and July 2020.ResultsPractices worked flexibly within general national guidance to determine when face-to-face contact with patients was necessary, influenced by knowledge of the patient, experience, and practice resilience. For example, practices prioritised patients according to clinical need using face-to-face contact to resolve clinician uncertainty or provide adequate reassurance to patients. To make face-to-face contact as safe as possible and keep patients separated, practices introduced a heterogeneous range of measures that exploited features of their indoor and outdoor spaces and altered their appointment processes. As national restrictions eased in June and July, the number and proportion of patients seen face-to-face generally increased. However, the reconfiguration of buildings and processes reduced the available capacity and put increased pressure on practices.ConclusionPractices responded rapidly and creatively to the initial lockdown restrictions. The variety of ways practices organised face-to-face contact to minimise infection highlights the need for flexibility in guidance.

Changes in potential cancer indicator reporting in primary-care during the COVID-19 pandemic (preprint)

Background In March 2020, the World Health Organisation declared COVID-19 a pandemic.Aim To investigate how the pandemic affected presentation to primary-care with features potentially indicating cancer, and explore how reporting differed by patient characteristics and in face-to-face vs. remote consultations.Design and setting Retrospective cohort study in 21 practices in South-West England.Methods Potential cancer indicators were identified using pre-defined code lists for symptoms, signs, test results and diagnoses. Negative binomial regression models compared reporting of potential cancer indicators in April-July 2020 to April-July 2019. Incidence rate ratios (IRRs), 95% confidence intervals (CIs) and p-values are reported.Results During April-July 2019 and 2020, respectively, 152,447/344,184 (44%) and 123,775/350,966 (35%) patients consulted, with 44,662/344,184 (13%) and 29,150/350,966 (8%) reporting a potential cancer indicator (IRR=0.65, 95%CI 0.62-0.68, p<0.001). Reduced indicator reporting was stable across ethnicity, deprivation and shielding status, was greater in children (0-4 years IRR=0.50, 95%CI 0.46-0.55, p<0.001; 5-17 years IRR=0.45, 95%CI 0.41-0.49, p<0.001) and males (IRR=0.61, 95%CI 0.58-0.64), and less marked in patients with mental health conditions (IRR=0.75, 95%CI 0.72-0.79, p<0.001). Indicator reporting dropped for GP face-to-face consultations (IRR=0.88, 95%CI 0.80-0.97, p=0.011) and increased for remote consultations (IRR=1.22, 95%CI 1.11-1.34, p<0.001), but despite this, remained lower in remote consulting than face-to-face in April-July 2020.Conclusion Patient consulting in general, and for potential cancer indicators specifically, reduced during the first-wave of the COVID-19 pandemic. Remote consulting may be part of the reason for the reduction in reporting of potential cancer indicators, along with the reduced spreading of viral (non-cancer) infections.

The implementation of remote consulting in UK primary care following the COVID-19 pandemic: a mixed-methods longitudinal study (preprint)

Background: To reduce contagion of COVID-19, in March 2020 UK general practices implemented predominantly remote consulting via telephone, video or online consultation platforms.Aim: To investigate the rapid implementation of remote consulting and explore impact over the initial months of the COVID-19 pandemic.Design and Setting: Mixed-methods study in 21 general practices in Bristol, North Somerset and South Gloucestershire.Methods: Quantitative: Longitudinal observational analysis comparing volume and type of consultations in April-July 2020 with April-July 2019. Negative binomial models were used to identify if changes differed amongst different groups of patients. Qualitative: 87 practice staff longitudinal interviews in four rounds investigated practices experience of the move to remote consulting, challenges faced and solutions. A thematic analysis utilised Normalisation Process Theory.Results: There was universal consensus that remote consulting was necessary. This drove a rapid change to 90% remote GP consulting (46% for nurses) by April 2020. Consultation rates reduced in April-July 2020 compared to 2019; GPs/nurses maintained a focus on older patients, shielding patients and patients with poor mental health. Telephone consulting was sufficient for many patient problems, video consulting was used more rarely, and was less essential as lockdown eased. SMS-messaging increased more than three-fold. GPs were concerned about increased clinical risk and some had difficulties setting thresholds for seeing patients face-to-face as lockdown eased.Conclusions: The shift to remote consulting was successful and a focus maintained on vulnerable patients. It was driven by the imperative to reduce contagion and may have risks; post-pandemic, the model may need adjustment.