The role of COVID-19 vaccines in preventing post COVID-19 thromboembolic and cardiovascular complications: a multinational cohort study

Importance The overall effects of vaccination on the risk of cardiac, and venous and arterial thromboembolic complications following COVID-19 remain unclear. Objective We studied the association between COVID-19 vaccination and the risk of acute and subacute COVID-19 cardiac and thromboembolic complications. Design Multinational staggered cohort study, based on national vaccination campaign rollouts. Setting Network study using electronic health records from primary care records from the UK, primary care data linked to hospital data from Spain, and national insurance claims from Estonia. Participants All adults with a prior medical history of ≥180 days, with no history of COVID-19 or previous COVID-19 vaccination at the beginning of vaccine rollout were eligible. Exposure Vaccination status was used as a time-varying exposure. Vaccinated individuals were classified by vaccine brand according to the first dose received. Main Outcomes Post COVID-19 complications including myocarditis, pericarditis, arrhythmia, heart failure (HF), venous (VTE) and arterial thromboembolism (ATE) up to 1 year after SARS-CoV-2 infection. Measures Propensity Score overlap weighting and empirical calibration based on negative control outcomes were used to minimise bias due to observed and unobserved confounding, respectively. Fine-Gray models were fitted to estimate sub-distribution Hazard Ratios (sHR) for each outcome according to vaccination status. Random effect meta-analyses were conducted across staggered cohorts and databases. Results Overall, 10.17 million vaccinated and 10.39 million unvaccinated people were included. Vaccination was consistently associated with reduced risks of acute (30-day) and subacute post COVID-19 VTE and HF: e.g., meta-analytic sHR 0.34 (95%CI, 0.27-0.44) and 0.59 (0.50-0.70) respectively for 0-30 days, sHR 0.58 (0.48 - 0.69) and 0.71 (0.59 - 0.85) respectively for 90-180 days post COVID-19. Additionally, reduced risks of ATE, myocarditis/pericarditis and arrhythmia were seen, but mostly in the acute phase (0-30 days post COVID-19). Conclusions COVID-19 vaccination reduced the risk of post COVID-19 complications, including cardiac and thromboembolic outcomes. These effects were more pronounced for acute (1-month) post COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough vs unvaccinated SARS-CoV-2 infection. Relevance These findings highlight the importance of COVID-19 vaccination to prevent cardiovascular outcomes after COVID-19, beyond respiratory disease. Question What is the impact of COVID-19 vaccination to prevent cardiac complications and thromboembolic events following a SARS-CoV-2 infection? Findings Results from this multinational cohort study showed that COVID-19 vaccination reduced risk for acute and subacute COVID-19 heart failure, as well as venous and arterial thromboembolic events following SARS-CoV-2 infection. Meaning These findings highlight yet another benefit of vaccination against COVID-19, and support the recommendations for COVID-19 vaccination even in people at high cardiovascular risk. ### Competing Interest Statement DPA's department has received grant/s from Amgen, Chiesi-Taylor, Lilly, Janssen, Novartis, and UCB Biopharma, the European Medicines Agency and the Innovative Medicines Initiative. His research group has received consultancy fees from Astra Zeneca and UCB Biopharma. Amgen, Astellas, Janssen, Synapse Management Partners and UCB Biopharma have funded or supported training programmes organised by DPA's department. RK's research group has received consultancy fees from AstraZeneca, and the Estonian Ministry of Social Affairs through the RITA CORIVA and RITA MAITT projects. AU reports funding from the European Regional Development Fund (RITA 1/02-120) for her institution. HN reports support from the European Health Data & Evidence Network (EHDEN) project grant, Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806968 for harmonization of the Norwegian registry data into OMOP CDM. TDS reports funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968 for the institute to map the SIDIAP data to the OMOP CDM. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. All other authors declare no conflict of interest. ### Funding Statement The research was supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC). DPA is funded through a NIHR Senior Research Fellowship (Grant number SRF-2018-11-ST2-004). Funding to perform the study in the SIDIAP database was provided by the Real World Epidemiology (RWEpi) research group at IDIAPJGol. Costs of databases mapping to OMOP CDM were covered by the European Health Data and Evidence Network (EHDEN). ### 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: The study was approved by the CPRD's Research Data Governance Process, Protocol No 21_000557 and the Clinical Research Ethics committee of Fundacio Institut Universitari per a la recerca a l'Atencio Primaria de Salut Jordi Gol i Gurina (IDIAPJGol) (approval number 4R22/133) and the Research Ethics Committee of the University of Tartu (approval No. 330/T-10). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes CPRD: CPRD data were obtained under the CPRD multi-study license held by the University of Oxford after Research Data Governance (RDG) approval. Direct data sharing is not allowed. SIDIAP: In accordance with current European and national law, the data used in this study is only available for the researchers participating in this study. Thus, we are not allowed to distribute or make publicly available the data to other parties. However, researchers from public institutions can request data from SIDIAP if they comply with certain requirements. Further information is available online () or by contacting SIDIAP (sidiap{at}idiapjgol.org). CORIVA: CORIVA data were obtained under the approval of Research Ethics Committee of the University of Tartu and the patient level data sharing is not allowed.