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

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. Question Is COVID-19 associated with higher long-term incidence of vascular diseases? Findings In this cohort study of 48 million adults in England and Wales, COVID-19 was associated with higher incidence, that declined with time since diagnosis, of both arterial thromboses [week 1: adjusted HR [aHR] 21.7 (95% CI 21.0-22.4) weeks 27-49: aHR 1.34 (1.21-1.48)] and venous thromboembolism [week 1: aHR 33.2 (31.3-35.2), weeks 27–49 1.80 (1.50-2.17)]. aHRs were higher, for longer, after hospitalised than non-hospitalised COVID-19. The estimated excess number of arterial thromboses and venous thromboembolisms was 10,500. Meaning Avoidance of COVID-19 infection through vaccination, and use of secondary preventive agents after infection in high-risk patients, may reduce post-COVID-19 acute vascular diseases. ### Competing Interest Statement WW is supported by the Chief Scientists Office (CAF/01/17) and Stroke Association (SA CV 20100018). WW has given expert testimony to UK courts. WW served on an advisory board for Bayer. NC receives funds from AstraZeneca to support membership of Data Safety and Monitoring Committees for clinical trials. ### Funding Statement This work was funded by the Longitudinal Health and Wellbeing COVID-19 National Core Study, which was established by the UK Chief Scientific Officer in October 2020 and funded by UK Research and Innovation (grant references MC\_PC\_20030 and MC\_PC\_20059), by the British Heart Foundation as part of the BHF Data Science Centre led by HDR UK (BHF grant number SP/19/3/34678), by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation(grant reference MC\_PC\_20058), and by the CONVALESCENCE study of long COVID, which is funded by NIHR/UKRI. This work uses data provided by patients and collected by the NHS as part of their care and support. We would also like to acknowledge all data providers who make anonymised data available for research. This work was supported by the Con-COV team funded by the Medical Research Council (grant number: MR/V028367/1). This work was supported by Health Data Research UK, which receives its funding from HDR UK Ltd (HDR-9006) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation (BHF) and the Wellcome Trust. This work was supported by core funding from the: British Heart Foundation (BHF; RG/13/13/30194; RG/18/13/33946), BHF Cambridge CRE (RE/13/6/30180) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) [*]. This work was supported by the ADR Wales programme of work. The ADR Wales programme of work is aligned to the priority themes as identified in the Welsh Governments national strategy: Prosperity for All. ADR Wales brings together data science experts at Swansea University Medical School, staff from the Wales Institute of Social and Economic Research, Data and Methods (WISERD) at Cardiff University and specialist teams within the Welsh Government to develop new evidence which supports Prosperity for All by using the SAIL Databank at Swansea University, to link and analyse anonymised data. ADR Wales is part of the Economic and Social Research Council (part of UK Research and Innovation) funded ADR UK (grant ES/S007393/1). This work was supported by the Wales COVID-19 Evidence Centre, funded by Health and Care Research Wales. SI was funded by a BHF-Turing Cardiovascular Data Science Award (BCDSA\100005) and is funded by a University College London FB Cancer Research UK Award (C18081/A31373). RK, JAC and JACS were supported by the NIHR Bristol Biomedical Research Centre. RK, VW GDS were supported by the MRC Integrative Epidemiology Unit at the University of Bristol. RK was supported by NIHR ARC West. RD and JACS were supported by Health Data Research UK. SK is funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). TM was funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). AMW is part of the BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No 116074 and was supported by the BHF-Turing Cardiovascular Data Science Award (BCDSA\100005). WW is supported by the Chief Scientists Office (CAF/01/17). CS, CS, MB AW and WW are supported by Stroke Association (SA CV 20\100018). *The views expressed are those of the author(s) and not necessarily those of the NIHR, UKRI or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval was obtained from the Newcastle & North Tyneside 2 Research Ethics Committee (20/NE/0161), the NHS Digital Data Access Request Service (DARS-NIC 381078-Y9C5K) and the British Heart Foundation Data Science Centre CVD-COVID UK Approvals and Oversight Board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data used in this study are available in NHS Digitals Trusted Research Environment (TRE) for England, and in the SAIL Databank at Swansea University, Swansea, UK, for Wales but as restrictions apply they are not publicly available. Pseudonymised data was accessed and analysed within privacy protecting trusted research environments (NHS Digital DAE and SAIL). The analysis was performed according to a pre-specified analysis plan with phenotyping and analysis code at github.com/BHFDSC/CCU002_01. All data produced in the present work are contained in the manuscript.