Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales

  1. Rochelle Knight
  2. Venexia Walker
  3. Samantha Ip
  4. Jennifer A. Cooper
  5. Thomas Bolton
  6. Spencer Keene
  7. Rachel Denholm
  8. Ashley Akbari
  9. Hoda Abbasizanjani
  10. Fatemeh Torabi
  11. Efosa Omigie
  12. Sam Hollings
  13. Teri-Louise North
  14. Renin Toms
  15. Xiyun Jiang
  16. Emanuele Di Angelantonio
  17. Spiros Denaxas
  18. Johan H. Thygesen
  19. Christopher Tomlinson
  20. Ben Bray
  21. Craig J. Smith
  22. Mark Barber
  23. Kamlesh Khunti
  24. George Davey Smith
  25. Nishi Chaturvedi
  26. Cathie Sudlow
  27. William N. Whiteley
  28. Angela M. Wood
  29. Jonathan A.C. Sterne
  30. for the CVD-COVID-UK/COVID-IMPACT Consortium and the Longitudinal Health and Wellbeing COVID-19 National Core Study

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Abstract

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear.

Methods:

We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history.

Results:

Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0–22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21–1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3–35.2) in week 1 to 1.80 (95% CI, 1.50–2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses.

Conclusions:

High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

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  1. Version published to 10.1161/circulationaha.122.060785
  2. ScreenIT

    SciScore for 10.1101/2021.11.22.21266512: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: Study oversight: 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.
    Sex as a biological variablenot detected.
    RandomizationFor computational efficiency, analyses included all people with the outcome of interest or with a record of COVID-infection, and a 10% randomly sampled subset of other people.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Analyses used SQL, Python and RStudio (Professional) Version 1.3.1093.1 driven by R Version 4.0.3 (2020-10-10).
    Python
    suggested: (IPython, RRID:SCR_001658)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This study has several limitations. First, the survival analyses allowed for variations in diagnoses with calendar time, so should control for the reductions in hospital attendance the period of maximum disruption (March and April 2020). However, some vascular events not have been recorded either because patients died in nursing homes with few diagnostic resources, or were so unwell that MI, stroke, PE or DVT diagnoses would have been difficult. Second, patients may have avoided healthcare after minor vascular events because of fear of COVID-19. If this was more likely in people without COVID-19, then estimated hazard ratios would have been biased upwards. Third, because the English primary care dataset did not include information on PE and DVT, the incidence of milder venous events may have been underestimated. Fourth, we had limited resolution to determine the date order of COVID diagnosis and arterial thromboses or VTE events for some hospitalised patients. Some patients hospitalised with a vascular event either developed a nosocomial infection or had a COVID-19 diagnosis after routine testing on admission. For some patients, a raised troponin with COVID-19 may have led to a diagnosis of MI.12 Therefore the very high hazard ratios within one week of COVID-19 diagnosis may have been inflated by reverse causality. Fifth, there was under-ascertainment of COVID-19 infection before testing for SARS-CoV-2 became widely available for mild or asymptomatic infections. Such underdia...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.11.22.21266512v1 on medRxiv