Does influenza vaccination contribute to the prevention of cardiovascular events?

Table 1: Characteristics of included systematic reviews and meta-analyses

Author, Year	Study design	PICO	Participant characteristics	Detailed outcome(s) definition	AMSTAR 2Footnote a
SRMA of RCT
Liu et al. 2024	N=5 (RCT) Time covered: Until September 2024	P: Adult patients with IHD I: Influenza vaccinated people C: Unvaccinated people O: MACE or other clinical events	5,659 patients with IHD (2,838 vaccinated, 2,821 controls) Median age: 57–66 years 67.8% males Median follow-up: 12 months	MACE or other clinical events (including cardiovascular death, all-cause mortality, MI, hospitalization for HF, and re-vascularization)	High
Omidi et al. 2023	N=5 (RCT) Time covered: Until August 1, 2023	P: Patients with a diagnosis of CVD I: Influenza vaccine C: Placebo O: CV events	9,059 patients (4,529 vaccinated, 4,530 controls) Mean age: 61.3 years Mean follow-up: 9 months	MACE Included the following: MI, stroke, and/or CV death	Low
Barbetta et al. 2023	N=5 (RCT) Time covered: Until September 2021	P: Patients with coronary artery disease I: Influenza vaccine C: Placebo or no vaccine O: Reported at least one of the specified CV outcomes	4,187 patients (2,098 vaccinated, 2,089 controls) Intervention group: Mean age: 54.9–65 years 61%–81.4% males Control group: Mean age of 54.5–67 years 52%–82.1% males	Primary outcomes: MACE: CV death, non-fatal MI, non-fatal stroke All cause mortality CV mortality Secondary outcomes: Hospitalization for HF, stroke or TIA, revascularization, ACS	Moderate
Modin et al. 2023	N=6 (RCT) Time covered: Until December 2022	P: Patients with high CV risk (ischaemic heart disease and/or HF) I: Influenza vaccine C: Placebo O: Incidence of CV outcomes assessed as efficacy outcomes	9,340 patients (4,670 vaccinated, 4,670 controls) Mean age: 54.5–67 years Follow-up: 9.8–36 months	Primary endpoints: Composite of CV death, acute coronary syndrome, stent thrombosis or coronary revascularization, stroke or HF hospitalization Secondary endpoints: CV death, all-cause death	Moderate
Behrouzi et al. 2022	N=6 (RCT) Time covered: 2000–2021	P: Patients with cardiac history I: Influenza vaccine C: Placebo and no treatment O: Major adverse CV events	9,001 patients (4,510 vaccinated, 4,491 controls) 42.5% females Mean age: 65.5 years Cardiac history: 52.3% Mean follow-up: 9 months	Primary outcomes: Composite of MACE (CV death or hospitalization for MI, unstable angina, stroke, heart failure, or urgent coronary revascularization) within 12 months of follow-up Secondary outcomes: CV mortality within 12 months of follow-up	Critically low
Diaz-Arocutipa et al. 2022	N=5 (RCT) Time covered: Until September 2021	P: Patients with coronary artery disease I: Influenza vaccine C: Placebo or standard care O: MACE, all-cause mortality, CV mortality, and MI	4,175 patients (2,110 vaccinated, 2,065 controls) 75% males Mean age: 54.5–67 years Follow-up: 6–12 months Comorbidities: hypertension (55%), previous MI (23%), and diabetes (22%)	Primary outcomes: MACE Secondary outcomes: All-cause mortality, CV mortality, MI	Moderate
Maniar et al. 2022	N=8 (RCT) Time covered: Until May 2022	P: Patients hospitalized for acute MI or HF I: Influenza vaccination within a specified timeframe after hospitalization for MI or HF C: No influenza vaccination, placebo, or delayed vaccination O: Reduction in MACE and CV mortality	14,420 patients Follow-up: 6–36 months	MACE, CV mortality, all-cause mortality, MI	Critically low
Clar et al. 2015	N=8 (RCT) Time covered: Until February 2015	P: Patients 18 years and older who may or may not have had a history of CVD I: Influenza vaccination C: Control treatment O: CV death or non-fatal CV events	12,029 patients (1,682 with known CVD and 10,347 from general population or elderly people) Follow-up: 42 days–1 year	Primary outcomes: Patients without previous CVD: first-time MI, first-time unstable angina, death from CV causes Patients with previous CVD: MI, Unstable angina, death from CV causes Secondary outcomes: Composite clinical outcomes	Moderate
Udell et al. 2013	N=6 (RCT) Time covered:Until August 2013	P: Patients with high CV risk I: Influenza vaccination C: Placebo or standard of care O: CV events (efficacy or safety events)	6,735 patients 51.3% females Mean age: 67 years Cardiac history: 36.2% Mean follow-up time: 7.9 months	MACE, CV mortality, all-cause mortality, individual nonfatal CV events (MI, stroke, HF, hospitalization for unstable angina or cardiac ischemia, and urgent coronary revascularization)	Moderate
SRMA of RCT and observational studies
Liu et al. 2024	N=6 (RCT) N=37 (Obs.) Time covered: Until September 2023	P: Adults (18+ years) from the general population or with established CVD I: Influenza vaccine C: Placebo or no vaccine O: All-cause or CV mortality, all-cause or CVD hospitalization	RCT: 12,662 participants Mean age, 62 years; 45% women; 8,797 (69%) with preexisting CVD Follow-up: 6–12 months Observational: 6,311,703 participants Mean age, 49 years; 50% women; 1,189,955 (19%) with pre-existing CVD	All-cause or CV mortality, all-cause or CVD hospitalization and CVD was defined as including any diagnoses relating to MI, HF, or stroke	High
Zahhar et al. 2024	Until December 2022 N=3 (RCT) N=23 (Obs.)	P: Patients >18 years I: Influenza vaccine C: No influenza vaccine O: Risk of stroke occurrence/hospitalization	6,196,668 patients total 42% of studies included patients ≥65 years	Incidence/hospitalization due to stroke (any stroke, ischemic stroke, hemorrhagic stroke) and mortality	Moderate
Liu et al. 2022	N=1 (RCT) N=6 (Obs.) Time covered: Until October 2021	P: Adults (>18 years) I: Influenza vaccine C: No influenza vaccine or received vaccine beyond the period of efficacy O: Risk of arrhythmia	RCT: 2,532 patients Mean age: 59.85 years 80.51% males Mean/median follow-up: 1 year Observational: 3,167,445 patients Age range: 18–73.3 years 55.9%–85.29% males Mean/median follow-up: 9 months–3.7 years	Arrhythmia: including AF, atrial flutter, ventricular fibrillation, ventricular flutter, cardiac arrest	Moderate
Zangiabadian et al. 2020	N=6 (RCT) N=11 (Obs.) Time covered: January 2000–November 2019	P: Patients aged 18+ years I: Influenza vaccine C: No influenza vaccine O: CV events	Total: 180,043 cases and 276,898 control 47% of studies included patients ≥65 years RCT: 3,677 cases, 3,681 controls Age range: 18+ years Cohort: 78,522 cases, 127,833 controls Age range: 31+ years Case-control: 97,844 cases, 145,384 controls Age range: 40+ years	Occurrence of CV events (CV death, non-fatal MI, non-fatal stroke, hospitalization for HF, coronary ischemic events, HF, vascular death)	Low
Gupta et al. 2023	N=6 (RCT) N=9 (Obs.) Time covered: 2000–2021	P: Patients with and without CVD I: Influenza vaccination C: No influenza vaccination O: CV outcomes	745,001 patients Mean age: 70.11 (vaccinated) and 64.55 (unvaccinated) years Mean follow-up time: 6 months–2 years 50% females (vaccinated); 41% females (unvaccinated)	All-cause mortality, CV death, stroke, MI, hospitalization for HF	Critically low
Jaiswal et al. 2022	N=5 (RCT) N=13 (Obs.) Time covered: Until April 2022	P: Patients with established CVD or at high CV risk I: Influenza vaccine C: No influenza vaccine or placebo O: All-cause mortality, MACE, HF, MI, CV mortality, stroke	22,532,165 patients total 217,072 with high CV risk or established CVD (111,073 vaccinated, 105,999 unvaccinated) Mean age: 68 years Mean follow-up: 1.5 years	Primary outcomes: All-cause mortality, MACE Secondary outcomes: HF, MI, CV mortality, stroke	Low
Yedlapati et al. 2021	N=4 (RCT) N=12 (Obs.) Time covered: Until January 2020	P: Patients with CVD (atherosclerotic CVD or HF) I: Influenza vaccine C: Placebo O: Mortality and CV outcomes	237,058 patients total (RCT: 1,667 patients, observational: 235,391 patients) Mean age: 69.2 ± 7.01 years 36.6% females Median follow-up: 19.5 months	All-cause mortality, CV mortality, MACE, HF, MI	Low
Cheng et al. 2020	N=6 (RCT) N=69 (Obs.) Time covered: Until November 2018	P: Adults I: Influenza vaccine C: Placebo O: CV and respiratory disease outcomes and all-cause mortality	4,419,467 patients total Follow-up: 4 months–9 years	CVD (including stroke, MACE, MI, HF, ischemic heart disease, transient ischemic attack, acute coronary syndrome, cardiac arrest, CV mortality, atrial fibrillation) and all-cause mortality	Low
Tsivgoulis et al. 2018	N=5 (RCT-all included influenza) N=6 (Obs.) Time covered: Until March 2017	P: Adult patients at risk of cerebrovascular ischemia I: Influenza vaccination C: No influenza vaccination or different types of vaccination O: Ischemic stroke and other CV outcomes	431,937 patients total Mean age range: 59.9 + 10.3 years and older 19.9%–59.7% vaccinated 38.9%–72.5% males Follow-up time range: 6 months–2 years	Primary outcomes: Cerebrovascular ischemia, specifically acute ischemic stroke Secondary outcomes: Myocardial ischemic events, CV deaths	High
Loomba et al. 2012	N=3 (RCT) N=2 (Obs.) Time covered: 1998–2011	P: Patients with cardiovascular disease or at risk of CV events I: Influenza vaccine C: No influenza vaccine O: CV morbidity and mortality	292,383 patients total (169,203 vaccinated and 123,481 unvaccinated) Mean age: 58–77 years 42.6–73.9% males	MI, all-cause mortality, and MACE	Critically low
SRMA of observational studies
Tavabe et al. 2023	N=14 (Obs.) Time covered: 1980–July 2021	P: Elderly I: Influenza vaccine C: No influenza vaccine O: Stroke and hospitalization occurrence	3,198,646 patients Mean follow-up: 30 months	Stroke occurrence or hospitalization due to stroke	Moderate
Gupta et al. 2022	N=7 (Obs.) Time covered: Until October 2021	P: Adult patients with heart failure I: Influenza vaccine C: No influenza vaccine O: All-cause mortality, CV-related mortality, all-cause hospitalization, CV-related hospitalization, non-fatal stroke, and non-fatal MI	247,842 patients Mean age: 68–77 years Male to female ratio close to 50% in most studies	All-cause mortality and hospitalization, CV mortality and hospitalization, non-fatal stroke, non-fatal MI within 12 months of receiving the influenza vaccine	Moderate
Rodrigues et al. 2020	N=6 (Obs.) Time covered: Until December 2018	P: Adult patients diagnosed with heart failure and/or if they had a reported abnormal/reduced ejection fraction (<50%) I: Influenza vaccination C: No influenza vaccination O: All-cause mortality, HF mortality, CV mortality, all-cause hospitalizations, CV hospitalization rates, HF-related hospitalization rates, hospitalization length and ventricular arrhythmias	179,158 patients Mean age: 62–75 years Follow-up: 3 months–8 years	Primary outcome: All-cause mortality Secondary outcomes: HF mortality, CV mortality, all-cause hospitalizations, CV hospitalization rates, HF-related hospitalization rates, hospitalization length and ventricular arrhythmias	High
Caldeira et al. 2019	N=2 (SCCS) Time covered: Until September 2019	P: Adult (18+ years) patients with a first recorded AMI in the study period and recorded influenza vaccination I: Influenza vaccination C: No influenza vaccination O: incidence rate of AMI	32,676 patients Median age: 72.3–77 years	Incident rate ratio of MI within first month (1–28 days) of influenza vaccination	Low
Lee et al. 2017	N=11 (Obs.) Time covered: Until November 2016	P: Individuals (18+ years) at risk of stroke I: Influenza vaccine C: No influenza vaccine O: Risk of stroke (any, first, recurrent)	593,513 patients 45% of studies included participants ≥60 years	Risk of stroke (any, first, recurrent)	Moderate
Barnes et al. 2015	N=7 (case-control) Time covered: Until June 2014	P: Adult patients with AMI I: Influenza vaccine C: Patients without AMI, including those who did and did not receive the influenza vaccine O: Fatal or non-fatal AMI, including first or subsequent episode(s)	17,695 cases with AMI (9,428 vaccinated) and 65,343 controls without AMI (33,819 vaccinated) Mean age: ≥40 years	Risk of AMI (first, recurrent). AMI was defined as a constellation of clinical features, including ischemic symptoms, biochemical and/or electrical evidence of myocardial ischemia, evidence of critical artery stenosis on coronary angiography or autopsy evidence of MI	Moderate

Figure 2: Descriptive text

CV outcomes	Systematic review and meta-analyses
CV mortality	60%
All-cause mortality	60%
MACE	52%
MI	44%
Stroke or TIA	36%
All-cause hospitalization	16%
HF	12%
CV hospitalization	12%
Arrythmia or ACS	8%
Revascularization	8%

Quality assessment and primary studies overlap

The quality assessment of each SRMA was performed using AMSTAR 2. This tool was adapted so that any item with a “no” response was classified as a critical flaw, while items with a “partial yes” response were not considered critical flaws. Overall, four SRMAs were deemed of “critically low” quality, six were of “low” quality, and a total of 15 SRMAs (60%) were deemed to be of “moderate” or “high” quality. Consequently, only the 15 SRMAs of “moderate” or “high” quality were included in the detailed summary of findings synthesis ^{Footnote 22Footnote 23Footnote 27Footnote 28Footnote 29Footnote 32Footnote 33Footnote 34Footnote 35Footnote 38Footnote 40Footnote 41Footnote 42Footnote 43Footnote 45}. The main items in which most SRMAs scored poorly were: not including a full list of excluded studies (item 7); the absence of a satisfactory technique for assessing the risk of bias in included individual studies (item 9); the use of appropriate methods in meta-analyses for statistical combination of results (item 11); and not accounting for the risk of bias in primary studies when discussing/interpreting the results (item 13) (Table S1).

Finally, the overlap between primary studies included in each SRMA was assessed further, and only two SRMA presented a 100% overlap between their primary studies (Table S2).

Summary of findings

The umbrella review resulted in the following findings:

• Cardiovascular mortality: A total of nine out of 15 (67%) SRMAs assessed CV-related mortality, eight were in patients with underlying CVD or at higher risk of CV events, ^{Footnote 22Footnote 28Footnote 29Footnote 34Footnote 35Footnote 38Footnote 40Footnote 43}, while one consisted of adults with or without CVD history ^{Footnote 28}. Overall, six SRMAs (67%) showed a significant reduction in CV mortality following influenza vaccination (Figure 3) ^{Footnote 22Footnote 27Footnote 28Footnote 29Footnote 35Footnote 38}. In adults with a higher risk of CV events, the risk of death due to a CV event was reduced by 23% (95% CI: 19%–27%) to 47% (95% CI: 26%–62%) in vaccinated individuals compared to those who were not vaccinated. The heterogeneity of these findings was low to moderate, ranging between 0% and 58%. Similarly, pooled data from four RCTs that included adults with or without CVD history showed a 55% (95% CI: 24%–74%) risk reduction in CV mortality, with no heterogeneity (I²: 0%). Conversely, results were not significant in three SRMAs, with moderate to critical heterogeneity (I²: 37%–94%) (Figure 3) ^{Footnote 34Footnote 40Footnote 43}.

Figure 3: Descriptive text

This forest plot illustrates the pooled effect measures from systematic review and meta-analyses examining the association between influenza vaccination and CV events. It includes data from multiple studies, primarily RCTs, focusing on populations at high risk for CV events. Each entry shows the number of CV events among vaccinated and unvaccinated individuals, along with heterogeneity statistics (I²). Overall, the plot visually summarizes the consistency and strength of evidence across studies.

• Major adverse cardiac events: MACE is a composite outcome endpoint that generally included: CV death, all-cause mortality, acute coronary syndrome (ACS), MI, hospitalization for a CV event, revascularization, stroke, and HF. Overall, five (33%) SRMAs assessed the effect of influenza vaccination on MACE outcomes in participants with high-risk of CV events. All were SRMAs of RCT, and their overall findings were consistently showing a 26% (95% CI: 12%–51%) to 37% (95% CI: 23%–49%) significant reduction in the risk of MACE in vaccinated individuals. The heterogeneity of these results was low to moderate (I²: 0%–47%) (Figure 3) ^{Footnote 22Footnote 28Footnote 35Footnote 38Footnote 43}.
• Myocardial infarction: The risk of MI following influenza vaccination was assessed in three (20%) SRMAs. Two were SRMAs of RCTs, whereas one included observational studies. Participants were at high-risk of CV events in all SRMAs. Findings showed a significant reduction in the risk of MI in vaccinated individuals, ranging between 29% (95% CI: 9%–44%) to 34% (95% CI: 7%–54%) with no heterogeneity (I²: 0%) ^{Footnote 24Footnote 36}, whereas another SRMA reported a 31% reduction in MI, although it did not reach statistical significance and had substantial heterogeneity (I²: 63%) (Figure 3) ^{Footnote 28}.
• Stroke: Stroke and transient ischemic heart attack (TIA) in influenza vaccinated individuals were evaluated in five (33%) SRMAs. Three of these SRMAs involved participants with high-risk for CV events ^{Footnote 22Footnote 32Footnote 42}, while two included adults and older adults ^{Footnote 41Footnote 45}. Other than one SRMA that was of RCTs only, the remaining SRMA included observational studies or both RCTs and observational studies. The overall risk reduction in stroke and TIA ranged between 13% (95% CI: 4%–21%) and 19% (95% CI: 14%–23%), and was statistically significant across four SRMAs, with substantial heterogeneity (I²: 53%–86%) (Figure 3).

Discussion

This review presents a comprehensive evidence synthesis from multiple published and robust SRMAs that assessed the association between influenza vaccination and CV events. Detailed pooled effect measures were reported for four main CV outcomes: CV mortality, MACE, MI and stroke/TIA. Most SRMAs reported a significant reduction in CV events following influenza vaccination, especially in individuals with underlying CVD, or at higher risk for CV events. Indeed, the risk for CV mortality was up to 47% lower in vaccinated individuals, whereas MACE was reduced by 37% and MI events by 34% compared to unvaccinated individuals. Finally, the risk of stroke/TIA was reduced by up to 19% in vaccinated individuals.

Interpretations

Influenza is well recognized as a trigger for CV outcomes, especially in the first two weeks following infection ^{Footnote 8}. The risk of CV exacerbation or complications following influenza infection is particularly high in individuals with pre-existing CVD ^{Footnote 47}. Thus, influenza vaccination stands out as a potentially effective intervention to reduce the burden of CV outcomes, especially among high-risk groups ^{Footnote 8Footnote 13}. Several mechanisms underlie the cardioprotective effects of influenza vaccination. While influenza triggers systemic inflammation, which can exacerbate atherosclerosis and CVD, the vaccine activates the immune system, enhancing overall immune health and preventing secondary infections that could worsen CV conditions. Additionally, it could help stabilize atherosclerotic plaques, thus reducing the risk of acute CV events, according to some earlier findings ^{Footnote 39}.

Altogether, the available evidence supports recommending annual influenza vaccination for high-risk individuals, particularly those with underlying CVD. This preventive measure can significantly reduce the risk of CV events and improve overall health outcomes in these populations.

However, despite the recommendations for individuals with chronic health conditions in Canada to be vaccinated ^{Footnote 14}, influenza vaccination coverage remains sub-optimal in these groups. During the 2023–2024 season, only 44.1% of adults aged 18–64 with chronic medical conditions were vaccinated against influenza, whereas the national goals for seasonal influenza in this population were to achieve 80% vaccination coverage ^{Footnote 48}.

Implications

An effective communication of influenza vaccine-associated benefits against specific outcomes could help foster vaccination ^{Footnote 49}. A large trial in Denmark titled Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU) investigated the effect of digital behavioural nudges on influenza vaccine uptake among individuals aged 65 years and older, with a focus on CVD status ^{Footnote 50}. Over 960,000 Danish citizens were randomized to usual care or one of nine electronically delivered letters, designed using behavioural concepts, prior to the 2022–2023 seasonal influenza vaccination period. One of these letters specifically emphasized the potential CV benefits of influenza vaccination. Interestingly, this CV-focused letter had the greatest effect on increasing vaccine uptake. The effect was consistent across individuals with and without CVD, as well as across CVD subgroups. This suggests that emphasizing CV benefits may be an effective strategy to boost vaccination rates, even among those without existing CVD ^{Footnote 50}.

Thus, clear communication about the potential CV benefits associated with influenza vaccination could help raise awareness and motivation to vaccinate among high-risk groups, who are already targeted for the annual vaccination campaign, about the usefulness of influenza vaccines. Nevertheless, since data on CV benefits are not usually included in studies analyzing the benefits of influenza vaccination and given the recent accumulation of studies on the subject, it would be interesting to consider this type of effect in future cost-effectiveness evaluations of influenza vaccines ^{Footnote 13}.

Limitations

Despite the strength of this evidence synthesis, this review possesses limitations inherent to included studies. First, the quality and heterogeneity of the included primary studies varied, which may influence the accuracy of pooled estimates. The observed heterogeneity could be attributable to differences in the study populations, CV outcomes definition, duration of follow-up and timing of vaccination. Secondly, many SRMAs included observational studies, which are prone to confounding bias. Finally, although associations were consistent, the causality of the effect cannot be ascertained, and large-scale RCTs are needed to further explore the cardioprotective effects of influenza vaccination.

Conclusion

In conclusion, this umbrella review provides a high-quality evidence synthesis supporting the CV benefits of influenza vaccination. The significant reductions in CV mortality, MACE, and stroke highlight the importance of promoting influenza vaccination, particularly among people with underlying chronic medical conditions, such as CVD. By integrating influenza vaccination into routine clinical practice and public health strategies, CV outcomes can be improved while reducing the burden of both CVD and influenza.

Authors’ statement

• FT — Conceptualization, data curation, visualization, formal analysis, writing–original draft
• NS — Validation, writing–review & editing
• WS — Validation, writing–review & editing
• PDP — Conceptualization, validation, writing–review & editing
• AS — Conceptualization, supervision, validation, writing–review & editing

Competing interests

None.

ORCID numbers

Fazia Tadount — 0009-0001-4867-5942
Winnie Siu — 0009-0001-5772-1509

Acknowledgements

We gratefully acknowledge the contribution of Katarina Gusic, Natalie Smith, and Richard Huang, for their assistance with data validation and quality assessment.

Funding

This work was supported by the Public Health Agency of Canada.

Appendix

Supplemental material is available upon request to the author: naci-ccni@phac-aspc.gc.ca

Supplemental A: Search strategy

Table S1: AMSTAR 2 detailed assessment

Table S2: Overlap between primary studies matrix

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