A national Danish study found that while influenza can sharply increase the short-term risk of heart attack and stroke, prior vaccination is associated with a significantly lower excess risk for those who remain infected.
Study: Influenza vaccination reduces the risk of acute myocardial infarction and stroke after influenza infection: a registry-based self-administered case series study, Denmark, 2014-2025. Image credit: Halfpoint / Shutterstock
In a recent registry-based study published in the journal euro monitoringResearchers investigated the short-term risk of acute myocardial infarction (AMI) and stroke after laboratory-confirmed influenza. This study utilized a self-controlled case series (SCCS) design to analyze data from 1,221 Danish residents.
Study results revealed a significant increase in cardiovascular events during the first 7 days after infection (IRR = 3.5). Importantly, previous seasonal vaccination was associated with a 50% reduction in this excess risk (interaction p = 0.020).
These findings suggest that influenza vaccination may reduce severe cardiovascular complications after breakthrough influenza infection, even if the vaccine fails to prevent primary viral infection.
Background of cardiovascular events caused by influenza
Cardiovascular disease (CVD) has long been the leading cause of human disability-adjusted life years worldwide. Two of the most common subvariants, ischemic heart disease (IHD) and stroke, are estimated to collectively account for approximately 3,095 disability-adjusted life years per 100,000 people.
Previous studies have demonstrated that influenza infection can cause CVD events. Studies have shown that influenza infection acts as an acute trigger of these events by inducing systemic inflammation, promoting a prothrombotic state (increased clotting tendency) and destabilizing vulnerable atherosclerotic plaques.
As a result, there is increasing mechanistic evidence suggesting that acute coronary syndrome or cerebral infarction often occurs shortly after the onset of influenza symptoms. A meta-analysis of randomized controlled trials (RCTs) showed that influenza vaccination reduced the overall risk of serious adverse cardiovascular events by 32%.
Unfortunately, most previous research in this area has focused on the ability of vaccines to prevent infection. Research regarding the potential for vaccines to alter the clinical course following infection (e.g., reducing the severity of the inflammatory response and subsequent cardiovascular triggers) remains uncertain.
Danish SCCS study design and population
This study aimed to address this knowledge gap and inform future vaccination policy by conducting a national self-controlled case series (SCCS) study with an overall study period of 2014-2025, using data obtained from the Danish National Health Registry over the 2015/16 to 2023/24 influenza seasons.
This study aimed to achieve methodological validity by comparing an individual’s risk during the exposure period to his or her own baseline risk. This enabled downstream statistical models to effectively control for time-invariant confounders such as hereditary and hereditary factors, participants’ socio-economic status, and potential pre-existing chronic comorbidities.
The study population included individuals aged 40 years and older (n = 1,221, 46% female, median age = 75 years) who experienced a first hospitalization for AMI or stroke (within 365 days of influenza infection confirmed by polymerase chain reaction (PCR)). The participants’ Danish National Health Register was deterministically linked (via participant-specific central personal registration CPR numbers) to additional datasets: the Danish Microbiology Database, the National Patient Register, and the Vaccination Register.
The primary risk period for this study was defined as days 1 to 7 after the date of influenza specimen collection. Furthermore, the 14 days before exposure were excluded to reduce reverse causality, thereby ensuring that hospitalizations caused by early influenza symptoms were not misclassified. The date of specimen collection was used as the exposure anchor as the date of symptom onset was not available.
AMI stroke risk after vaccination and influenza
The study’s primary analysis identified 53 cardiovascular events in the risk period (crude incidence rate: 2.28 events per person-year) compared with 1,168 events in the control period (0.53 events per person-year). After adjusting for calendar month (seasonal variation), the pooled adjusted incidence rate ratio (IRR) was 3.5 (95% CI: 2.6 to 4.7). Risk was observed to be significantly higher for the incidence 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 analyzes were stratified by participants’ vaccination status, results revealed that the IRR for unvaccinated episodes was 4.7, significantly higher than the IRR for vaccinated episodes (2.4). The ratio of these IRRs (0.51) suggests that vaccination reduced almost half of the excess cardiovascular risk associated with infection (p = 0.020). Subgroup analysis further characterized the risk profile and showed that the IRR reached 5.2 on days 1–3 postinfection and decreased on days 15–28 (IRR = 1.2).
Of note, this study found that women had a higher relative incidence of post-influenza cardiovascular events (IRR = 4.7) compared to men (IRR = 2.5), although vaccination appeared to be protective across both groups. However, the authors noted that the results for these subgroups should be interpreted with caution.
The findings were investigated using Campylobacter spp. Infectious disease as a negative exposure control. This gastrointestinal pathogen also increased cardiovascular risk (IRR = 3.2), but influenza vaccination showed no protective interaction (interaction p = 0.60). This supports the interpretation that the observed attenuation is specific to influenza viruses.
Influenza vaccination and its impact on cardiovascular prevention
The study found that influenza infection temporarily but significantly increased the risk of first heart attack or stroke, concentrated in the first week of illness. Encouragingly, vaccination was found to significantly reduce this excess cardiovascular risk in the event of a breakthrough case.
Future studies that integrate annual vaccine efficacy data may further refine these risk estimates and provide more targeted public health recommendations, especially given that vaccine efficacy may vary seasonally.
