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Meta-Analysis
. 2022 Apr 1;5(4):e228873.
doi: 10.1001/jamanetworkopen.2022.8873.

Association of Influenza Vaccination With Cardiovascular Risk: A Meta-analysis

Bahar Behrouzi  1   2   3 , Deepak L Bhatt  4 , Christopher P Cannon  4 , Orly Vardeny  5 , Douglas S Lee  1   2   6 , Scott D Solomon  4 , Jacob A Udell  1   2   3   6
Affiliations
Meta-Analysis

Association of Influenza Vaccination With Cardiovascular Risk: A Meta-analysis

Bahar Behrouzi et al. JAMA Netw Open. .

Abstract

Importance: Influenza infection is associated with increased cardiovascular hospitalization and mortality. Our prior systematic review and meta-analysis hypothesized that influenza vaccination was associated with a lower risk of cardiovascular events.

Objective: To evaluate, via an updated meta-analysis, if seasonal influenza vaccination is associated with a lower risk of fatal and nonfatal cardiovascular events and assess whether the newest cardiovascular outcome trial results are consistent with prior findings.

Data sources: A previously published meta-analysis of randomized controlled trials (RCTs) and a large 2021 cardiovascular outcome trial.

Study selection: Studies with RCTs published between 2000 and 2021 that randomized participants to either influenza vaccine or placebo/control. Eligible participants were inpatients and outpatients recruited for international multicenter RCTs and randomized to receive either influenza vaccine or placebo/control.

Data extraction and synthesis: PRISMA guidelines were followed in the extraction of study details, and risk of bias was assessed using the Cochrane Collaboration tool. Trial quality was evaluated using Cochrane criteria. Data were analyzed January 2020 and December 2021.

Main outcomes and measures: Random-effects Mantel-Haenszel risk ratios (RRs) and 95% CIs were derived for a composite of major adverse cardiovascular events and cardiovascular mortality within 12 months of follow-up. Where available, analyses were stratified by patients with and without recent acute coronary syndrome (ACS) within 1 year of randomization.

Results: Six published RCTs comprising a total of 9001 patients were included (mean age, 65.5 years; 42.5% women; 52.3% with a cardiac history). Overall, influenza vaccine was associated with a lower risk of composite cardiovascular events (3.6% vs 5.4%; RR, 0.66; 95% CI, 0.53-0.83; P < .001). A treatment interaction was detected between patients with recent ACS (RR, 0.55; 95% CI, 0.41-0.75) and without recent ACS (RR, 1.00; 95% CI, 0.68-1.47) (P for interaction = .02). For cardiovascular mortality, a treatment interaction was also detected between patients with recent ACS (RR, 0.44; 95% CI, 0.23-0.85) and without recent ACS (RR, 1.45; 95% CI, 0.84-2.50) (P for interaction = .006), while 1.7% of vaccine recipients died of cardiovascular causes compared with 2.5% of placebo or control recipients (RR, 0.74; 95% CI, 0.42-1.30; P = .29).

Conclusions and relevance: In this study, receipt of influenza vaccination was associated with a 34% lower risk of major adverse cardiovascular events, and individuals with recent ACS had a 45% lower risk. Given influenza poses a threat to population health during the COVID-19 pandemic, it is integral to counsel high-risk patients on the cardiovascular benefits of influenza vaccination.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms Behrouzi reported receiving funding from a University of Toronto MD/PhD studentship award and the Ted Rogers Centre for Heart Research Education Fund, and receiving grant support to her institutions from Boehringer Ingelheim, Lilly, and Sanofi-Aventis. Dr Bhatt reported grant funding from Abbott, Affimmune, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Contego Medical, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories/AstraZeneca, Fractyl, Garmin, HSL Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Owkin, Pfizer Inc, Regeneron, Roche, Sanofi Aventis, Stasys, Synaptic, The Medicines Company, and 89Bio; he reported receiving personal fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP Global, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, TobeSoft, Bayer, Medtelligence/ReachMD, CSL Behring, MJH Life Sciences, Level Ex, K2P, Canadian Medical and Surgical Knowledge Translation Research Group, Arnold and Porter law firm, and Piper Sandler; other from FlowCo, Takeda, Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Clinical Cardiology, VA, St Jude Medical (now Abbott), Biotronik, Merck, Svelte, CSI, Philips; grants and other from PLx Pharma, Boston Scientific, CellProthera, Cardax, PhaseBio, Novo Nordisk, Cereno Scientific, MyoKardia/BMS, Janssen, Novo Nordisk, Novartis, NirvaMed; personal fees, nonfinancial support, and other from American College of Cardiology; personal fees and nonfinancial support from Society of Cardiovascular Patient Care and American Heart Association; and grants, personal fees, and other from Boehringer Ingelheim. Dr Cannon reported receiving grants and personal fees from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck and Co, and Pfizer Inc; grants from Daiichi Sankyo and Better Therapeutics; personal fees from Aegerion/Amryt, Alnylam, Amarin, Applied Clinical Therapeutics, Ascendia, Eli Lilly, Rhoshan, Sanofi, Lexicon; and grants and other from Novo Nordisk. Dr Vardeny reported receiving grants from AstraZeneca and Bayer and personal fees from Novartis. Dr Solomon reported receiving grants from Novartis, Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos; and personal fees from Abbott, Actelion, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GSK, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Sanofi Pasteur, Tenaya, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent. Dr Lee reported appointment as the Ted Rogers Chair in Heart Function Outcomes, University Health Network, at the University of Toronto. Dr Udell reported receiving support from a Government of Ontario Early Researcher Award (grant No. ER15-11-037), Women’s College Research Institute and Department of Medicine, Women’s College Hospital; he reported receiving grant support to his institutions from AstraZeneca, Novartis, and Sanofi; he reported service as a consultant for Amgen, Boehringer Ingelheim, Janssen, Merck, Novartis, and Sanofi; and he has received honoraria from Boehringer Ingelheim and Janssen. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Major Adverse Cardiovascular Events for Influenza Vaccine vs Control When Comparing 2021 Large Cardiovascular Outcome Trial With Previous Meta-analysis
Square data markers represent risk ratios; horizontal lines, 95% CIs, with marker size reflecting the statistical weight of the study using random-effects meta-analysis. Diamond data markers represent each subgroup and overall risk ratio with 95% CIs for the outcome of interest. Evaluated using the random-effects Mantel-Haenszel test. Heterogeneity variance τ2 calculated using the DerSimonian-Laird estimator. Risk of bias evaluated using standard Cochrane criteria: A, random sequence generation (selection bias); B, allocation concealment (selection bias); C, masking of participants and personnel (performance bias); D, masking of outcome assessment (detection bias); E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias. Red indicates high risk of bias, yellow indicates unclear risk of bias, and green indicates low risk of bias.
Figure 2.
Figure 2.. Major Adverse Cardiovascular Events Comparing Influenza Vaccine vs Control Stratified by History of Recent Acute Coronary Syndrome (ACS)
Square data markers represent risk ratios; horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. Diamond data markers represent each subgroup and overall risk ratio and 95% CIs for the outcome of interest. Evaluated using the random-effects Mantel-Haenszel test. Heterogeneity variance τ2 calculated using the DerSimonian-Laird estimator.
Figure 3.
Figure 3.. Cardiovascular Mortality Comparing Influenza Vaccine vs Control Stratified by History of Recent Acute Coronary Syndrome (ACS)
Square data markers represent risk ratios; horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. Diamond data markers represent each subgroup and overall risk ratio and 95% CIs for the outcome of interest. Evaluated using the random-effects Mantel-Haenszel test. Heterogeneity variance τ2 calculated using the DerSimonian-Laird estimator.
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