Investigating the effect of influenza vaccine on acute cardiovascular events by cardiovascular risk status

Date of Approval: 
2021-05-26 00:00:00
Lay Summary: 
In the days after severe influenza infection, people are at higher risk of an acute cardiovascular event, such as a heart attack or stroke. Influenza vaccine can prevent influenza infection or reduce the severity of illness. Vaccination can, therefore, also prevent any acute cardiovascular event which may occur after infection. Clinical trials have previously shown that in people who have pre-existing cardiovascular disease (e.g., heart disease or a previous stroke), the influenza vaccine reduces the chance of further cardiovascular events. It is unknown whether the vaccine offers the same protection to people who have risk factors for cardiovascular disease (without having pre-existing cardiovascular disease), such as in those with high blood pressure. Anonymised GP and hospital records are often used to measure the real-world effectiveness of vaccines. We will use records from adults aged 40-84 years to estimate the occurrence of first acute cardiovascular events following influenza vaccination compared to an event without recent influenza vaccination. We will do this separately for people with and without risk factors for cardiovascular disease. In England, routine seasonal influenza vaccine is offered to all people aged ≥65 years and those aged <65 years in a clinical risk group more likely to experience infection-related complications. Our study will include all adults aged 40-84 who receive influenza vaccine as individuals <65 years with risk factors for cardiovascular disease (our population of interest) are not typically targeted for influenza vaccine.
Technical Summary: 
Observational studies have identified that acute respiratory infections can trigger acute cardiovascular events, particularly myocardial infarction and stroke. In self-controlled case series (SCCS) studies, which implicitly control for the effect of fixed confounding factors using within-individual comparisons, myocardial infarction and stroke risk were elevated two- to six-fold in the days following clinically diagnosed respiratory infections and influenza-like illness, with this elevated risk remaining for up to one month. Consistent cardiovascular triggering effects have been found for laboratory-confirmed infections, including the influenza virus. Randomized controlled trials and observational studies have also demonstrated the cardiovascular benefit of the seasonal influenza vaccine. However, randomized controlled trial data is largely limited to individuals with established cardiovascular disease (CVD). While observational studies have considered the vaccine's benefit among those without a previous cardiovascular event, the benefit specifically in people with raised cardiovascular risk has not been considered. Quantifying any protective effects of influenza vaccine in people with raised cardiovascular risk, predictive of future CVD, will further understanding of the vaccine’s cardiovascular benefits and whether it is effective for primary prevention of CVD. We aim to investigate the association between influenza vaccination and major adverse cardiovascular events in a SCCS study, focusing on the effect of raised cardiovascular risk level, defined by QRISK2 score ≥10% and diagnosed hypertension, on any association. We will use CPRD Aurum and HES admissions data from 2008-2019 and include all adults aged 40-84 years who had seasonal influenza vaccine and experienced their first major adverse cardiovascular event in the same year as vaccination was given. SCCS design removes between-person confounding, a major issue in vaccine effectiveness studies using observational data. In conditional Poisson regression models adjusted for season, we will calculate incidence ratios. We will also stratify by patient cardiovascular risk status.
Health Outcomes to be Measured: 
We will use the same primary and secondary cardiovascular outcomes as detailed in our ISAC protocol no. 19_209, with the exception of cardiovascular death (note death excluded as an outcome due to SCCS design in which an event of interest must not censor the observation period, see "Data/statistical analysis" and "Limitations" sections for further details). Primary outcome: First major adverse cardiovascular events (MACE). This includes; acute coronary syndrome (ACS) which captures both myocardial infarction (MI) and unstable angina, stroke, transient ischaemic attack (TIA), left ventricular heart failure and acute limb ischaemia. Secondary outcomes: Individual cause-specific acute cardiovascular events: • acute coronary syndrome (subdivided into MI and unstable angina), • stroke / TIA, • left ventricular heart failure.
Application Number: 

Charlotte Warren-Gash - Chief Investigator - London School of Hygiene & Tropical Medicine ( LSHTM )
Jennifer Davidson - Corresponding Applicant - London School of Hygiene & Tropical Medicine ( LSHTM )
Amitava Banerjee - Collaborator - University College London ( UCL )
Clémence Leyrat - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Emily Herrett - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Helen McDonald - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Ian Douglas - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Liam Smeeth - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )

HES Admitted Patient Care;ONS Death Registration Data;Patient Level Townsend Score