A nationwide Danish study found that flu can sharply raise the short-term risk of heart attack and stroke, while prior vaccination was linked to a markedly lower excess risk in people who still became infected.
Study: Influenza vaccination attenuates acute myocardial infarction and stroke risk following influenza infection: a register-based, self-controlled case series study, Denmark, 2014 to 2025. Image Credit: Halfpoint / Shutterstock
In a recent register-based study published in the journal Eurosurveillance, researchers investigated the short-term risk of acute myocardial infarction (AMI) and stroke following laboratory-confirmed influenza. The study leveraged a self-controlled case series (SCCS) design to analyze data from 1,221 Danish residents.
Study findings revealed a significant rise in cardiovascular events during the first seven days post-infection (IRR = 3.5). Crucially, prior seasonal vaccination was associated with a 50% reduction in this excess risk (interaction p = 0.020).
These findings suggest that influenza vaccination may attenuate severe cardiovascular complications after breakthrough influenza infection, even when the vaccine fails to prevent the primary viral infection.
Influenza-Triggered Cardiovascular Event Background
Cardiovascular diseases (CVD) have long remained the leading global cause of human disability-adjusted life-years. Two of its most common subvariants, ischaemic heart disease (IHD) and stroke, are together estimated to account for about 3,095 disability-adjusted life-years per 100,000 people.
Previous research has established that influenza infections can trigger CVD events. Studies have shown that influenza infection acts as an acute trigger for these events by inducing systemic inflammation, which promotes a pro-thrombotic state (increased clotting tendency) and destabilizes vulnerable atherosclerotic plaques.
Consequently, a growing body of mechanistic evidence suggests that the onset of influenza symptoms is often followed shortly by acute coronary syndrome or cerebral infarction. Meta-analyses of randomized controlled trials (RCTs) indicated that influenza vaccination reduces the overall risk of major adverse cardiovascular events by 32%.
Unfortunately, most previous research in the field has focused on the vaccine’s ability to prevent infection. Research into vaccines’ potential to modify the post-infection clinical course (e.g., reducing the severity of the inflammatory response and subsequent cardiovascular triggers) remains uncertain.
Danish SCCS Study Design and Population
The present study aimed to address this knowledge gap and inform future vaccination policy by conducting a nationwide self-controlled case series (SCCS) study using data obtained from the Danish National Health Registries across influenza seasons from 2015/16 to 2023/24, with an overall study period spanning 2014 to 2025.
The study aimed to achieve methodological validity by comparing an individual’s risk during an exposure period to their own baseline risk. This allowed downstream statistical models to effectively control for time-invariant confounders, including genetic and heritable factors, participants’ socioeconomic status, and potential preexisting chronic comorbidities.
The study population included individuals aged ≥ 40 years (n = 1,221; 46% female; median age = 75 years) who experienced their first-ever hospital admission for AMI or stroke (within 365 days of a polymerase chain reaction (PCR)- confirmed influenza infection). Participants’ Danish National Health Registries were linked deterministically (via their unique Central Person Register CPR numbers) to additional datasets from the Danish Microbiology Database, National Patient Register, and Vaccination Register.
The study’s primary risk period was defined as days 1–7 following the influenza specimen collection date. Additionally, a 14-day pre-exposure period was excluded to mitigate reverse causality, thereby ensuring that hospitalizations prompted by early flu symptoms were not misclassified. Because symptom onset dates were unavailable, the specimen collection date was used as the exposure anchor.
Vaccination and Post-Influenza AMI Stroke Risk
The study’s primary analysis identified 53 cardiovascular events during the risk period (crude incidence: 2.28 per person-year), compared with 1,168 events during the control periods (0.53 per person-year). After adjusting for calendar month (seasonal variations), the pooled adjusted incidence rate ratio (IRR) was 3.5 (95% CI: 2.6–4.7). The risk was observed to be significantly higher for incidences of AMI (IRR = 4.7; 95% CI: 3.1–7.4) than for stroke (IRR = 2.9; 95% CI: 2.0–4.2).
When study analyses were stratified by participants’ vaccination status, outcomes revealed that IRRs for unvaccinated episodes were 4.7, significantly higher than IRRs for vaccinated episodes (2.4). The ratio of these IRRs (0.51) suggests that vaccination attenuated nearly half of the excess cardiovascular risk associated with the infection (p = 0.020). Subgroup analyses further characterized the risk profile, showing a peak IRR of 5.2 during days 1–3 post-infection, which subsided by days 15–28 (IRR = 1.2).
Notably, the study found that females had a higher relative incidence of post-influenza cardiovascular events (IRR = 4.7) compared to males (IRR = 2.5), though vaccination appeared protective across both groups. However, the authors noted that these subgroup findings should be interpreted cautiously.
Study findings were also examined using Campylobacter spp. infection as a negative exposure control. While this gastrointestinal pathogen also increased cardiovascular risk (IRR = 3.2), influenza vaccination showed no protective interaction (interaction p = 0.60), supporting the interpretation that the observed attenuation is specific to the influenza virus.
Influenza Vaccination and Cardiovascular Prevention Implications
The present study reveals that influenza infection triggers a transient but significant surge in the risk of first-time heart attacks and strokes, concentrated in the first week of illness. Encouragingly, vaccination was found to substantially attenuate this excess cardiovascular risk when breakthrough cases occur.
Future research integrating annual vaccine effectiveness data could further refine these risk estimates and inform more targeted public health recommendations, particularly given that vaccine effectiveness can vary across seasons.
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