COVID-19 booster vaccine effectiveness in secondary prevention of major adverse cardiovascular events: an emulated target trial in observational data

Study type
Date of Approval
Study reference ID
Lay Summary

Previous studies have shown that individuals have a higher risk of heart and brain attacks after contracting COVID-19. This study aims to determine if a booster vaccination for COVID-19 can prevent such attacks in people who have already experienced heart or brain attacks in the past (the so called “high-risk” population). We will use routine care data from the first UK booster campaign. We will compare “high-risk” individuals who received a booster vaccine to those who have not yet received it, using advanced statistical methods to account for any differences between the groups. We will estimate the difference between obtaining a booster vaccine and not obtaining a booster vaccine in the risk of heart and brain attacks after 24 weeks. Our findings could help inform policy makers about the benefit of COVID-19 booster vaccinations. For example, we currently know that the yearly flu shot can prevent heart and brain attacks in patients with heart and circulatory disease. In this study we may find out whether that also holds true for the COVID-19 booster.

Technical Summary

Literature suggests that COVID-19 increases the risk of major adverse cardiovascular events (MACE). Current debates focus on yearly COVID-19 booster vaccination in high-risk populations with the aim to reduce morbidity and mortality. The current study aims to answer the research question: What is the effectiveness of COVID-19 booster vaccination on MACE reduction in individuals with a history of cardiovascular disease? The study is designed to emulate sequential target trials in observational routine care data from the United Kingdom’s Clinical Practice Research Datalink (Aurum/HES).
Patients with existing cardiovascular disease aged 40 years or older who were eligible for booster (third dose) COVID-19 vaccination in the period of September to December 2021 will be included. Participants receiving a third vaccine dose (intervention) or not (yet) receiving a third vaccine dose (controls) will be compared on the 24-week risk difference in MACE (composite of stroke and myocardial infarction) with all-cause mortality as competing risk.

Data will be analyzed as sequentially emulated trials. Within each calendar week, all eligible individuals will be enrolled to either the intervention group (if they received the booster that week) or the control group (if they had not received the booster up to that week) and followed-up until MACE, death, loss to follow-up (censoring), protocol deviation (if individuals in the control group receive the booster) or the maximum follow-up duration of 24 weeks. Inverse probability weighting will be used to adjust for baseline differences between treatment arms, and potential time-varying confounding due to loss to follow-up or protocol deviation, using pooled logistic regression to determine the weights. The total effect of booster vaccination will be estimated using a weighted non-parametric cumulative incidence function, deriving absolute risk differences and risk ratios for MACE within 12 and 24 weeks of follow-up in the presence of all-cause death as competing event.

Health Outcomes to be Measured

Major adverse cardiovascular events consisting of myocardial infarction and ischemic or hemorrhagic stroke; All-cause mortality


Patrick Souverein - Chief Investigator - Utrecht University
Patrick Souverein - Corresponding Applicant - Utrecht University
Geert-Jan Geersing - Collaborator - University Medical Centre Utrecht
Hannah la Roi-Teeuw - Collaborator - University Medical Centre Utrecht
Helga Gardarsdottir - Collaborator - Utrecht University
Jungyeon Choi - Collaborator - University Medical Centre Utrecht
Maarten van Smeden - Collaborator - University Medical Centre Utrecht
Sander van Doorn - Collaborator - University Medical Centre Utrecht
Sophie Bots - Collaborator - Utrecht Institute for Pharmaceutical Sciences


HES Admitted Patient Care;Patient Level Index of Multiple Deprivation