Highlights
In more than 1 million vaccinated veterans, receiving the 2024-2025 COVID-19 vaccine alongside influenza vaccine was associated with a 37.7% lower risk of COVID-19-associated MACE at 8 months.
The absolute benefit was small overall, but larger in older adults: participants older than 75 years experienced the clearest relative and absolute risk reduction.
Secondary analyses suggested substantially larger reductions in all-cause MACE, hospitalization, and death, raising the possibility that vaccination prevents both recognized and unrecognized SARS-CoV-2–related morbidity.
As with all observational studies, the findings support association rather than definitive causation and should be interpreted alongside trial data, biologic plausibility, and patient-specific risk.
Background: Why This Question Matters Now
Cardiovascular complications remain a clinically important consequence of SARS-CoV-2 infection. Acute infection can trigger myocardial injury, arrhythmia, myocarditis, thromboembolism, stroke, heart failure decompensation, and vascular inflammation. Even as population immunity has increased through prior infection and earlier vaccination, older adults and people with chronic illnesses continue to experience disproportionate risk of severe COVID-19 and its downstream sequelae.
Early in the pandemic, vaccination was linked to fewer COVID-19 complications, including cardiovascular events. However, the 2024-2025 season introduced a new question: does the updated vaccine still provide meaningful cardiovascular protection in a population with widespread prior immunity and in the setting of evolving variants? This issue matters because the benefit of vaccination may no longer be captured only by prevention of symptomatic infection or hospitalization; it may also include reduction of occult or underdiagnosed SARS-CoV-2–related cardiovascular injury.
The present study addressed this gap using a large Veterans Affairs cohort, a setting with linked longitudinal clinical data and a high prevalence of older adults and multimorbidity. Those features make the VA an informative environment for assessing not only infection-related outcomes, but also broader cardiovascular consequences.
Study Design and Methods
This was a cohort study using target-trial emulation methods, an approach designed to mimic key features of a randomized trial using observational data. The investigators identified US Department of Veterans Affairs patients with vaccination encounters between September 3, 2024, and December 31, 2024.
The exposure was same-day coadministration of the 2024-2025 COVID-19 vaccine with influenza vaccine, compared with influenza vaccine alone. This comparison is pragmatic and clinically relevant because many adults receive both vaccines during the same visit, and influenza vaccination provides a useful active comparator that partially aligns healthcare-seeking behavior across groups.
The primary endpoint was a composite of COVID-19-associated MACE, defined as cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure occurring in the context of COVID-19. Secondary outcomes included all-cause MACE, all-cause hospitalization, and death. Vaccine effectiveness was estimated as 1 minus the risk ratio, and risk differences were calculated at 8 months using inverse probability weighting to reduce confounding.
The study included 1,039,659 participants who received influenza vaccination. Of these, 349,085 received the COVID-19 vaccine and 690,574 did not. The mean age was 70.1 years, and 91.8% were men, reflecting the demographic profile of the VA population.
Key Findings
Primary outcome: COVID-19-associated MACE
At 8 months, receipt of the 2024-2025 COVID-19 vaccine was associated with a lower risk of COVID-19-associated MACE. The estimated vaccine effectiveness was 37.7% with a 95% confidence interval of 18.2% to 54.9%. The absolute risk difference was 2.0 fewer events per 10,000 persons, with a 95% confidence interval of 0.9 to 3.7.
These estimates deserve careful interpretation. The relative reduction is clinically meaningful, but the absolute event rate was low, so the number of events prevented per 10,000 vaccinated individuals was modest. For population-level policy, even small absolute reductions may matter when applied to millions of older adults at elevated baseline risk. For individual patients, the benefit is most compelling when baseline cardiovascular and infectious risk are high.
Age-stratified effects
The strongest signal appeared in participants older than 75 years, where vaccine effectiveness for COVID-19-associated MACE reached 50.7% (95% CI, 31.8% to 65.6%). This age group also had the largest absolute benefit, with 5.5 fewer events per 10,000 individuals.
By contrast, no statistically significant vaccine effectiveness was observed among those younger than 65 years or between 65 and 75 years. This pattern is biologically and epidemiologically plausible. Older adults are more likely to have severe acute COVID-19, more baseline atherosclerotic and structural heart disease, and less physiologic reserve to tolerate infection-related inflammatory stress. When baseline risk is lower, absolute benefit naturally shrinks even if relative effects remain similar.
Comorbidity-stratified effects
Relative vaccine effectiveness for COVID-19-associated MACE was statistically significant in participants both with and without comorbid health conditions. However, the absolute reduction was consistently larger in those with comorbidities. This is an important public health point: the people who stand to gain most from vaccination are often those with the greatest burden of chronic disease, including diabetes, chronic kidney disease, established cardiovascular disease, and other conditions that amplify vulnerability to severe infection and post-infectious complications.
Secondary outcomes
Secondary analyses suggested substantially larger absolute risk reductions for all-cause outcomes than for the COVID-19-associated composite. The reported risk difference for all-cause MACE was 23.7 per 10,000 persons (95% CI, 14.1 to 34.7), indicating a much broader association than the strictly COVID-linked endpoint alone. Reductions in all-cause hospitalization and all-cause death were also observed.
These secondary findings are clinically provocative. They raise the possibility that vaccination is preventing a larger burden of downstream illness than what is captured by narrowly adjudicated COVID-19-associated cardiovascular events. Possible explanations include prevention of symptomatic and asymptomatic SARS-CoV-2 infection, attenuation of disease severity, reduction in unrecognized infection-triggered cardiovascular destabilization, and fewer acute-care cascades in frail older adults.
How Should Clinicians Interpret These Results?
The most conservative interpretation is straightforward: in a large cohort of US veterans, receiving the updated COVID-19 vaccine was associated with fewer cardiovascular events linked to COVID-19, especially among adults older than 75 years and those with comorbidities. That is an important finding because it supports the idea that updated vaccination still offers clinically relevant protection even in the current era of repeated exposures and evolving variants.
At the same time, the absolute reduction in COVID-19-associated MACE was modest. Clinicians should therefore avoid overstating the magnitude of benefit for any single patient, particularly younger adults with fewer comorbidities. The strongest rationale for vaccination remains in older adults and those with cardiovascular risk factors or other chronic disease.
The larger reduction in all-cause MACE is hypothesis-generating and clinically interesting, but it also warrants caution. Such outcomes may reflect a mixture of direct biologic effects, indirect protection from infection, differences in health behavior, and residual confounding despite advanced analytic methods. Observational studies can approximate a trial, but they cannot fully reproduce randomization.
Study Strengths
This analysis has several strengths. First, the sample size exceeded one million participants, providing substantial statistical power and allowing meaningful subgroup analyses. Second, the VA electronic health record system supports longitudinal capture of diagnoses, hospitalizations, and mortality. Third, the target-trial emulation framework improves causal interpretability compared with conventional retrospective cohort analysis. Fourth, the active-comparator design using influenza vaccine recipients helps partially balance healthcare engagement between groups.
Important Limitations
Several limitations should temper interpretation. The study population was predominantly older men, limiting generalizability to women, younger adults, pregnant individuals, and community-dwelling populations outside the VA system. Residual confounding remains possible, particularly if individuals who chose to receive the COVID-19 vaccine differed systematically in frailty, preventive care behavior, prior infection history, or unmeasured social determinants of health.
Outcome classification is another issue. The term COVID-19-associated MACE depends on identifying cardiovascular events in the context of COVID-19, which may be sensitive to testing behavior, documentation practices, and healthcare access. If vaccinated individuals were less likely to be tested or diagnosed with SARS-CoV-2, some events may have been misclassified. Conversely, if vaccinated persons were healthier or more engaged with care, effect estimates could be biased in either direction depending on the pattern of ascertainment.
Finally, because exposure was defined as same-day coadministration with influenza vaccine, the comparison may not perfectly isolate the effect of the COVID-19 vaccine alone. Nevertheless, this is a pragmatic real-world question and a reasonable approximation of seasonal vaccination behavior.
Mechanistic Plausibility
The association between COVID-19 vaccination and fewer cardiovascular events is biologically plausible. SARS-CoV-2 infection promotes endothelial dysfunction, cytokine-mediated inflammation, thrombosis, plaque destabilization, autonomic imbalance, and myocardial stress. By reducing infection risk and/or severity, vaccination may reduce the probability of these downstream cardiovascular triggers. In older adults with pre-existing coronary disease or heart failure, even a transient systemic infection can precipitate decompensation. Preventing that inflammatory insult may therefore have disproportionate clinical value.
Clinical and Public Health Implications
For clinicians, the study reinforces a pragmatic message: updated COVID-19 vaccination remains relevant not only for preventing respiratory disease, but also for mitigating cardiovascular complications in older and medically complex adults. In shared decision-making, this may be particularly useful when counseling patients who are motivated by cardiovascular protection or who are hesitant because they perceive vaccination benefit to be limited in a highly immune population.
For health systems and policy makers, the findings support targeted efforts to improve vaccine uptake among adults older than 75 years and among patients with chronic comorbidities. These are the groups most likely to realize meaningful absolute benefit. In settings with constrained resources, prioritization strategies should emphasize those with the highest baseline risk.
Conclusion
In this large VA target-trial emulation, receipt of the 2024-2025 COVID-19 vaccine was associated with a reduced risk of COVID-19-associated MACE, with the most convincing benefit in adults older than 75 years and in those with comorbid disease. The absolute reduction for the COVID-19-specific cardiovascular endpoint was modest, but the larger reduction in all-cause cardiovascular and mortality outcomes suggests that the vaccine may protect against a broader, and partly hidden, burden of SARS-CoV-2–related illness.
These findings strengthen the case for seasonal COVID-19 vaccination in older adults with cardiovascular vulnerability, while also underscoring the need for further studies in more diverse populations and with complementary randomized or quasi-experimental designs.
Funding and Trial Registration
The source abstract does not provide funding details. A clinicaltrials.gov registration number was not reported, consistent with an observational target-trial emulation study rather than a prospectively registered interventional trial.
References
1. Cai M, Xie Y, Al-Aly Z. 2024-2025 COVID-19 Vaccine and Major Adverse Cardiovascular Events Among US Veterans. JAMA Intern Med. 2026-06-15. PMID: 42295793.
2. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28(3):583-590.
3. Bowe B, Xie Y, Al-Aly Z. Acute and postacute sequelae associated with SARS-CoV-2 infection. Nat Med. 2021;27(6):904-914.
4. European Society of Cardiology guidance documents and contemporary public health recommendations on COVID-19 vaccination in older adults and high-risk patients may provide additional context, though local guidance should be consulted for seasonal recommendations.
