Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England
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Abstract
Thromboses in unusual locations after the Coronavirus Disease 2019 (COVID-19) vaccine ChAdOx1-S have been reported, although their frequency with vaccines of different types is uncertain at a population level. The aim of this study was to estimate the population-level risks of hospitalised thrombocytopenia and major arterial and venous thromboses after COVID-19 vaccination.
Methods and findings
In this whole-population cohort study, we analysed linked electronic health records from adults living in England, from 8 December 2020 to 18 March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous, and thrombocytopenic outcomes 1 to 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, age 2 , sex, ethnicity, and deprivation. We also prespecified adjustment for anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of pulmonary embolism or deep vein thrombosis, and history of coronavirus infection in analyses of venous thrombosis; and diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of myocardial infarction in analyses of arterial thromboses. We selected further covariates with backward selection.
Of 46 million adults, 23 million (51%) were women; 39 million (84%) were <70; and 3.7 million (8.1%) Asian or Asian British, 1.6 million (3.5%) Black or Black British, 36 million (79%) White, 0.7 million (1.5%) mixed ethnicity, and 1.5 million (3.2%) were of another ethnicity. Approximately 21 million (46%) adults had their first vaccination between 8 December 2020 and 18 March 2021.
The crude incidence rates (per 100,000 person-years) of all venous events were as follows: prevaccination, 140 [95% confidence interval (CI): 138 to 142]; ≤28 days post-ChAdOx1-S, 294 (281 to 307); >28 days post-ChAdOx1-S, 359 (338 to 382), ≤28 days post-BNT162b2-S, 241 (229 to 253); >28 days post-BNT162b2-S 277 (263 to 291). The crude incidence rates (per 100,000 person-years) of all arterial events were as follows: prevaccination, 546 (95% CI: 541 to 555); ≤28 days post-ChAdOx1-S, 1,211 (1,185 to 1,237); >28 days post-ChAdOx1-S, 1678 (1,630 to 1,726), ≤28 days post-BNT162b2-S, 1,242 (1,214 to 1,269); >28 days post-BNT162b2-S, 1,539 (1,507 to 1,572).
Adjusted HRs (aHRs) 1 to 28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and ≥70 years, respectively, were 0.97 (95% CI: 0.90 to 1.05) and 0.58 (0.53 to 0.63) for venous thromboses, and 0.90 (0.86 to 0.95) and 0.76 (0.73 to 0.79) for arterial thromboses. Corresponding aHRs for BNT162b2 were 0.81 (0.74 to 0.88) and 0.57 (0.53 to 0.62) for venous thromboses, and 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75) for arterial thromboses. aHRs 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 of thrombocytopenia in adults aged <70 years were higher 1 to 28 days after ChAdOx1-S (aHRs 2.27, 95% CI: 1.33 to 3.88 and 1.71, 1.35 to 2.16, respectively), but not after BNT162b2 (0.59, 0.24 to 1.45 and 1.00, 0.75 to 1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1 to 28 days after ChAdOx1-S were 0.9 to 3 per million, varying by age and sex.
The main limitations of the study are as follows: (i) it relies on the accuracy of coded healthcare data to identify exposures, covariates, and outcomes; (ii) the use of primary reason for hospital admission to measure outcome, which improves the positive predictive value but may lead to an underestimation of incidence; and (iii) potential unmeasured confounding.
Conclusions
In this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults aged <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine compared with unvaccinated, suggesting that either vaccine is suitable in this age group.
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SciScore for 10.1101/2021.08.18.21262222: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by 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 Sex as a biological variable Cox models were fitted separately by age group (<70 and ≥70 years), both overall and separately for males and females. Randomization For computational efficiency, each model included data from all people with, and a 10% random sample of people without, the outcome of interest; analyses incorporated inverse probability weights to account for this sampling. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sen… SciScore for 10.1101/2021.08.18.21262222: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by 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 Sex as a biological variable Cox models were fitted separately by age group (<70 and ≥70 years), both overall and separately for males and females. Randomization For computational efficiency, each model included data from all people with, and a 10% random sample of people without, the outcome of interest; analyses incorporated inverse probability weights to account for this sampling. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Data manipulation and analyses used SQL and Python in Databricks and RStudio (Professional) Version 1.3.1093.1 driven by R Version 4.0.3. 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:Our study has several limitations. First, identification of exposures, covariates and outcomes relies on the accuracy of data collected during routine healthcare. Additional data on results of laboratory and radiology investigations would have improved diagnostic coding, particularly for ascertainment of thrombocytopenia. Second, people who were not registered with an NHS GP (for example the homeless, recent immigrants, those using only private healthcare and those not eligible for NHS care) or who opted out of their data being provided to NHS Digital were excluded. Third, follow up ended on March 18th 2021, but a small number of events that occurred before this date may have been excluded because they had yet to be coded or the people affected were still in hospital. Analyses after this date will likely lead to overestimation of associations, because speciality societies recommended further investigations of mild symptoms in vaccinated populations. Fourth, our primary outcome used the primary reason for death or hospital admission, which improves the positive predictive value but may lead to an underestimation of incidence. This is necessary because historical non-incident events are frequently recorded in secondary positions. Analyses of events recorded in any position as fatal within 28 days were consistent with the primary analyses. Fifth, we did not address time-varying confounding, which can occur when factors which vary during follow up, such as admission to hospital, ...
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