Association of COVID-19 with arterial and venous vascular diseases: a population-wide cohort study of 48 million adults in England and Wales
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Abstract
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 1 st to December 7 th 2020.
Setting and participants
Adults registered with an NHS general practice in England or Wales and alive on January 1 st 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.
Key points
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.
Article activity feed
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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
Ethics IRB: 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 variable not detected. Randomization For 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. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Analyses used SQL, Python and RStudio (Professional) Version 1.3.1093.1 … 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
Ethics IRB: 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 variable not detected. Randomization For 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. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Analyses used SQL, Python and RStudio (Professional) Version 1.3.1093.1 driven by R Version 4.0.3 (2020-10-10). Pythonsuggested: (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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