http://dx.doi.org/10.7775/rac.v91.i1.20605
ORIGINAL ARTICLE
Effect of Influenza Vaccination in
Patients with Cardiovascular Disease: An Updated Meta-Analysis of Randomized
Controlled Trials
Efecto de la vacunación contra la influenza en pacientes con
enfermedad cardiovascular: un metaanálisis actualizado de ensayos clínicos
controlados aleatorizados
Lucrecia
M. Burgos1, Ezequiel J. ZaidelMTSAC,
2, Álvaro Sosa LiprandiMTSAC,
2, Adrián Baranchuk3
1 Department of Heart Failure,
Pulmonary Hypertension and Heart Transplantation, Instituto Cardiovascular de
Buenos Aires, Argentina
2 Department of Cardiology. Sanatorio Güemes,
Argentina, and School of Medicine, University of Buenos Aires.
3 Department of Cardiology, Kingston
Health Science Center, Queen’s University, Kingston, Ontario, Canada
Address for reprints: Lucrecia María Burgos. lburgos@icba.com.ar. Instituto Cardiovascular de Buenos Aires, Blanco Encalada
1543, CABA. CP1428
SEE RELATED ARTICLE: Argent J Cardiol 2021:89:1-4. http://dx.doi.org/10.7775/rac.v91.i1.20593
This article received the Dr. Pedro Cossio Award in
the 48º Argentine Congress of Cardiology
ABSTRACT
Background: Influenza is a major cause of
morbidity and mortality in patients with cardiovascular disease (CVD). The aim
of this updated systematic review and meta-analysis was to evaluate the effect
of influenza vaccination (IV) on morbidity and morbidity in adult patients with
CVD.
Methods: We conducted a systematic review and
meta-analysis (PubMed, Cochrane Library, International Clinical Trials Registry
Platform, and manual search of conference presentations) of randomized clinical
trials published up to April 2022 analyzing whether IV reduced all-cause
mortality in adult patients with CVD, including heart failure (HF) and coronary
artery disease (CAD), compared with patients who were not vaccinated.
Results: A total of six clinical trials
comprising 9316 patients were analyzed. Five trials included CAD patients, and
one trial included HF patients. Mean follow-up was 16 ± 9.7 months. Influenza
vaccine was associated with a reduction of mortality compared to controls:
relative risk (RR) 0.67, 95% confidence interval (95% CI), 0.47-0.95; p = 0.03;
I2
=
53%, and with reduction of cardiovascular death compared to controls: RR 0.64;
95% CI 0.44-0.94; p = 0.02; I2 = 54%. There was a non-statistically significant
reduction in myocardial infarction compared to control: RR 0.82, 95% CI
0.60-1.12; p = 0.57; I2 = 0%.
Conclusion: In this meta-analysis of six
randomized controlled clinical trials, IV was associated with a 33% and 36%
relative risk reduction of all-cause mortality and cardiovascular death,
respectively, in patients with CVD. We sought to promote consensus about the
persistent benefits of influenza vaccination in patients with CVD by including
two new clinical trials in CAD and HF, confirming the association of
vaccination with risk reduction in subjects with CVD.
Keywords: Influenza - Influenza Vaccines -
Cardiovascular Diseases/Mortality - Myocardial Infarction
RESUMEN
Introducción:
La influenza es una causa
importante de morbilidad y mortalidad en pacientes con enfermedades cardiovasculares
(ECV). El objetivo de esta revisión sistemática actualizada y metaanálisis fue
evaluar los efectos de la vacunación contra la influenza (VI) sobre la
mortalidad y morbilidad en pacientes adultos con ECV.
Métodos:
Se realizó una revisión
sistemática y un metaanálisis (PubMed, Cochrane Library, International Clinical
Trials Registry Platform, y búsqueda manual en presentaciones en congresos de
la especialidad), de ensayos clínicos aleatorizados publicados hasta abril de
2022 que investigaron si la VI reduce la mortalidad por todas las causas en
pacientes adultos con ECV, incluyendo insuficiencia cardíaca (IC) y enfermedad
de las arterias coronarias (EAC), en comparación con pacientes que no fueron
vacunados.
Resultados:
Se analizaron un total de
seis ensayos clínicos, que incluyeron 9316 pacientes. Cinco ensayos incluyeron
pacientes con EAC, y uno con IC. El seguimiento medio fue de 16 ± 9,7 meses. La
VI se asoció con una reducción de la mortalidad en comparación con el control,
cociente de riesgos (RR) 0,67, intervalo de confianza del 95% (IC95%) 0,47-0,95; , p = 0,03; I2
= 53%; y con una reducción de la
mortalidad cardiovascular en comparación con el control, RR 0,64; IC95%
0,44-0,94; p = 0,02; I2
= 54%. El uso de la VI se asoció con
una reducción no estadísticamente significativa de infarto de miocardio en
comparación con el control, RR 0,82; IC95% 0,60-1,12; p = 0,57; I2 =
0%.
Conclusión:
En este metaanálisis de
seis ensayos controlados aleatorizados, la VI se asoció con una reducción del
riesgo relativo del 33% y del 36% de la mortalidad por todas las causas y
cardiovascular, respectivamente, en pacientes con ECV. Intentamos promover un
consenso con respecto a los beneficios persistentes de la vacuna contra la
influenza en pacientes con ECV, incluyendo dos nuevos ensayos clínicos en EAC e
IC, donde se confirma la asociación de la vacunación con la reducción de riesgo
en sujetos con ECV.
Palabras
clave: Gripe Humana - Vacunas
contra la Influenza - Enfermedades Cardiovasculares/Mortalidad - Infarto del
Miocardio
Received: 11/22/2022
Accepted: 12/13/2022
INTRODUCTION
Although influenza is primarily
considered a viral infection usually limited to the respiratory system, several
cardiovascular complications have been described. (1) Cardiovascular
disease (CVD) and influenza have been associated for a long time due to an
overlap in the peak incidence of each disease in the winter months. (2)
Epidemiological studies observed an increase in cardiovascular (CV) mortality
during influenza outbreaks, indicating that CV complications of influenza,
including exacerbation of heart failure (HF), acute ischemic heart disease,
and, less often, other CV manifestations (stroke, cardiac arrhythmias, venous
thromboembolism, or myocarditis), are important contributors to morbidity and
mortality during influenza virus infection. (3)
The connection between heart disease
and influenza is complex: it can occur via the inflammation-thrombosis pathway,
direct effects of the virus on the myocardium, or exacerbation of pre-existing
CV disease. (4) The mechanisms postulated to explain
the increased risk of vascular events include precipitating plaque rupture,
endothelial dysfunction, triggering of other latent infections contributing to
plaque rupture, triggering of the procoagulant pathway, tachycardia and
vasodilation associated with fever, and infection-related metabolic disorders,
including elevated triglyceride and blood glucose levels. (5,6)
Influenza vaccination (IV) is a
well-established strategy for reducing influenza-related morbidity and
mortality patients with CVD. (7,8) Based on
observational studies and randomized clinical trials, vaccination has been
associated with significant reductions in all-cause mortality and major adverse
cardiovascular events. (9-12)
Currently, the World Health
Organization, the Centers for Disease Control and Prevention, the American
Heart Association/American College of Cardiology, and the European Society of
Cardiology recommend annual influenza vaccination for patients with established
CVD. (13-15) In 2021, the Inter- American Society
of Cardiology published a consensus statement on IV and CVD, (16) citing the
most recent meta-analysis with 4 randomized clinical trials that showed that IV
was associated with a reduction in cardiovascular events, (17) and another
meta-analysis based on observational data from HF patients, which had
consistent findings. (18)
Because two new clinical trials have
been recently published in the last two years, we decided to perform an updated
meta-analysis of randomized clinical trials on the impact of IV on CV mortality
and outcomes in patients with CVD.
OBJECTIVE
Our primary objective was to perform
a systematic review and meta-analysis of randomized clinical trials to evaluate
the effect of IV on mortality in patients with CVD. The secondary objective was
to evaluate the effect of IV on CV mortality, myocardial infarction, and major
adverse cardiovascular events (MACE) in patients with HF and coronary artery
disease (CAD).
METHODS
The PRISMA (Preferred Reporting Items
for Systematic Reviews and Meta-Analyses) checklist was used to perform and
report this systematic review. (19)
Search method for identification of
studies
A systematic search was conducted to
identify articles published up to April 2022 in MEDLINE (PubMed database), the
Cochrane Library, and the International Clinical Trials Registry Platform. We
searched the following keywords or MESH terms in the title or abstract:
"influenza," "influenza vaccine," "vaccine,"
"myocardial infarction," "coronary artery disease,"
"acute coronary syndrome," "heart failure," and
"congestive heart disease".
We performed manual searches checking
the reference list of all the relevant publications to ensure complete collection
of relevant articles, and we also reviewed recent presentations at
international cardiovascular congresses.
Selection of relevant studies for
inclusion
Two reviewers (LMB, EJZ)
independently screened titles and abstracts to identify potentially relevant
articles. Any discrepancy in the data collected was resolved via discussion.
Full-text articles were included in this review if they met all the following
inclusion criteria: (1) randomized clinical trials comparing influenza vaccination
with placebo or no intervention when data on one of the outcomes were reported;
(2) articles providing data on the effectiveness of influenza vaccination in
patients with HF or CAD compared with an unvaccinated control group; (3)
influenza vaccination was administered within one year after study enrollment;
(4) articles published in English or Spanish language.
We excluded duplicates, studies that
included patients with different doses of influenza vaccination but without an
unvaccinated arm, and all nonrandomized controlled trials.
Type of participants
Participants >18 years with
established CVD; HF or (CAD stable or unstable angina and ST-segment elevation
or non- ST-elevation myocardial infarction) were included in the study.
Outcome measures
The primary outcome measure was
all-cause mortality, while the secondary outcome measure was CV mortality,
myocardial infarction, and major adverse cardiovascular events (MACE) among
vaccinated and unvaccinated patients with HF and CAD.
Data collection and management
Two reviewers independently extracted
data and all disagreements were resolved by discussion or arbitration. The
following data were systematically extracted:
− Trial characteristics:
design, duration, region, scope, year of publication.
− Intervention: type and method
of vaccination, control intervention.
− Participants: number of
participants, inclusion and exclusion criteria, total number and number in comparison
groups, baseline characteristics (age, sex, cardiovascular risk factors,
cardiovascular medication).
− Results: primary and
secondary outcomes according to trial, myocardial infarction or reinfarction,
unstable angina, cardiovascular death, and related outcomes.
Any discrepancy in data extraction
was resolved via discussion with another author (ASL).
Subgroup analysis
A subgroup analysis was performed to
compare the effects of vaccination on mortality in patients with HF and CAD.
Bias assessment
Bias was independently assessed by
two investigators. We assessed evidence of bias of randomized controlled trials
with the Cochrane risk of bias tool, (20,21) with evaluation of the following
criteria: random sequence generation (adequate method), allocation concealment,
blinding of participants and personnel, management of incomplete outcome data,
loss to follow-up or withdrawal from the study, intention-to-treat analysis,
selective reporting, similarity in baseline characteristics, any other observed
biases.
Measures of treatment effect
All outcome measures were dichotomous
results and were presented as risk ratios (RR) at the last follow-up reported.
Heterogeneity assessment
Heterogeneity between trials was
quantified with the I2 statistics, which is independent of
the number of studies in a meta-analysis, and with the chi-square test, with
significance levels set at a value of p = 0.1. An I2 value >
50% meant significant heterogeneity between studies. (22)
Data synthesis
Based on heterogeneity test, the
pooled RR was calculated using fixed effects model when there was no
heterogeneity and random effects model in case of heterogeneity.
Statistical analysis
All outcome measures were dichotomous
results and were presented as risk ratios (RR) and 95% confidence intervals
(95% CI) at the last follow-up reported.
Two-tailed p value < 0.05 was
considered statistically significant.
Publication bias was estimated in
case there were more than 10 studies by visual assessment in the funnel plot.
Egger's regression test was used to examine the asymmetry of the funnel plot. (23)
The selection process was carried out
using the Reference Manager Rayyan QCRI. (24) All data extracted from the
included studies were entered into Review Manager (RevMan 5.3).
Ethical considerations
This review does not contain any
direct interaction with human participants.
RESULTS
Search results
A total of 957 studies were
identified through literature search; 527 studies were selected and 486 were
excluded after an initial screening of titles and abstracts. The remaining 41
publications were reviewed in full text and evaluated according to the
inclusion criteria. Finally, 6 trials were selected for the quantitative
analysis. (25-30)
The search and selection process is
represented in a PRISMA flow diagram (Figure 1).
Fig. 1. PRISMA flow diagram for the selection procedure for
elegible studies.
Characteristics the studies included
A total of six clinical trials
comprising 9316 patients were analyzed. Five trials included CAD patients
(FLUVACS, FLUCAD, IVCAD, IAMI and Phrommintikul et al.), and the IVVE trial
included HF patients. Mean follow-up was 16 ± 9.7 months. Table 1 summarizes
the main general characteristics of the trials. A description of each study
included in the meta-analysis can be found in Table 1 of the supplementary
material.
Table 1.
Characteristics of the studies included in the meta-analysis.
Studies |
Patients |
Age, mean (SD) |
Men,
% |
Follow-up, months |
Control therapy |
N° in the control cohort |
Nº in the
intervention group |
Region |
FLUVACS 2004 (25) |
ACS (66%) or stable CAD and planned PCI (34%) |
65 (NR) |
79.4% |
12 |
Without treatment |
147 |
145 |
Argentina |
FLUCAD
2008 (26) |
56% with stable CAD, 24% with PCI for ACS, 20% with PCI for stable
angina |
60 (10) |
72.5% |
12 |
Placebo |
333 |
325 |
Poland |
IVCAD 2009 (27) |
Hospitalized patients and outpatients with recent ACS or stable CAD |
55 (9) |
66% |
12 |
Placebo |
131 |
135 |
Iran |
Phrommintikul
et al., 2011 (28) |
47%,
36% STEMI, 16% with
unstable angina |
66 (9) |
56% |
12 |
Without
treatment |
218 |
221 |
Thailand |
IAMI 2021 (29) |
Hospitalized patients and outpatients with recent ACS (STEMI 54.4%,
NSTEMI 45.3%) or high-risk stable CAD (0.3%) |
59,9 (11,2) |
81.8% |
12 |
Placebo |
1260 |
1272 |
Sweden, Denmark, Norway, Latvia, United Kingdom, Czechia,
Bangladesh, Australia |
IVVE
2022 (30) |
Symptomatic NYHA functional class II-IV heart failure |
57 (NR) |
49% |
36 |
Placebo |
2569 |
2560 |
India,
China, Africa |
ACS: acute coronary syndrome; CAD: coronary artery
disease; NR: not reported; NSTEMI: non-ST-segment elevation myocardial
infarction; NYHA: New York Heart Association; PCI: percutaneous coronary
intervention; SD: standard deviation; STEMI: ST-segment elevation myocardial
infarction.
Risk of bias in included studies
Risk of bias across studies is shown
in Figure 1 of the supplementary material, and risk of bias within studies is
shown in Figure 2 of the supplementary material.
Effects of influenza vaccination
Primary outcome measure: All-cause
mortality.
Influenza vaccine was associated with
lower mortality compared to control: RR 0.67, 95% CI 0.47-0.95; p = 0.03; I2 = 53% (Figure 2).
Fig. 2. Forest plot
of the effect of influenza vaccine versus placebo on all-cause mortality
Secondary outcome measure:
Cardiovascular death, myocardial infarction and MACE
Influenza vaccine was associated with
lower cardiovascular death compared to control: RR 0.64, 95% CI 0.44-0.94; p =
0.02; I2 = 54% (Figure 3), and with
reduction of MACE: RR 0.69, 95% CI 0-53-0.90; p = 0.007; I2 = 68% (Figure 4). There was
a non-statistically significant reduction in myocardial infarction compared to
control: RR 0.82, 95% CI 0.60-1.12; p = 0.57; I2 = 0% (Figure 5).
Fig. 3. Forest plot of the effect of influenza vaccine versus placebo on
cardiovascular death.
Fig. 4. Forest plot of the effect of influenza vaccine versus placebo on
MACE.
Fig. 5. Forest plot of the effect of influenza vaccine versus placebo on
myocardial infarction.
Subgroup analysis
A subanalysis of overall mortality
was performed comparing IV vs. control, stratified by history of CAD and HF. This
effect was not consistent between the two study populations: in HF, RR 0.91
(95% CI 0.80-1.02; p = 0.1) and in CAD RR 0.56 (95% CI 0.41-0.76; p = 0.0002),
p for interaction = 0.004. (Figure 3 of the supplementary material).
DISCUSSION
In this updated meta-analysis of
controlled clinical trials including 9316 patients with CAD or HF, IV was
associated with a significant reduction in all-cause mortality, cardiovascular
death, and MACE. Vaccinated patients presented a non-significant reduction in
the incidence of acute myocardial infarction.
The information about the association
of influenza and CVD is conclusive, but its mechanisms are still under study.
Yet, the inflammation-thrombosis model seems to be the most widely accepted
one. Other factors, such as increased metabolic demand due to the adrenergic
surges and hyperdynamic CV response, and hypoxia secondary to pulmonary
infection also seem to play an important role. (31,32)
Since the pioneering study conducted
in Argentina by Gurfinkel et al. was published in 2004 (25) and then
incorporated as the main and only evidence in the CDC guidelines in the United
States in 2009, (33) IV has been gradually established as
a prevention strategy for CV events.
Some recognized limitations to
broaden the use of IV include uncertainty about external validity, reproducibility
in different regions, climates, and high and low resource countries, and the
safe use in the setting of an acute event or its efficacy in subjects with HF.
These factors led to the development of the new clinical trials evaluated here.
In addition, although the
recommendation for IV is not new, it is still sub-optimally accepted. In the
United States, only 50% of patients with CAD received IV, with important
disparities according to socioeconomic determinants. (34) Similarly,
one third of those hospitalized for HF did not receive IV. (35)
We compared the results of our
meta-analysis with those of previous publications. A Cochrane review published
in 2015 of four secondary prevention trials included 1682 patients with CVD and
reported reduction in CV mortality (RR 0.45; 95% CI, 0.26- 0.76), but not in
AMI. (36) More recently, in 2021 a
meta-analysis of these four randomized trials and 12 observational studies
including more than 237 000 patients with CVD, reported that influenza
vaccination was associated with significant reductions in the risk of all-cause
mortality, CV mortality, and MACE at a median follow-up of 20 months. (17)
We believe that the main findings of
this meta-analysis are confirming that the benefit of reducing all-cause
mortality and cardiovascular death and the trend towards a reduction in the
risk of myocardial infarction remains after including new randomized clinical
trials involving more than 7000 subjects. The benefit in reducing events is
also maintained when two populations that were not previously evaluated are included
in the meta-analysis: subjects with a recent coronary event (IAMI trial) and
subjects with heart failure (IVVE trial).
As for the IAMI study, (29) the
indication of IV in subjects with coronary artery disease was supported by different
clinical trials and previous meta-analyses; however, the authors proposed the
strategy of indicating IV during hospitalization due to an acute coronary
event, demonstrating the safety and efficacy of this average age was 57 years,
and the patients came from low- and middle-income countries in Asia and Africa.
The authors of the IVVE study reported a reduction in outcomes as all-cause
mortality, cardiovascular death, and MACE during periods of peak circulation of
influenza, and a trend towards a reduction in events throughout the duration of
the study. Rather than a neutral result, this finding reinforces the pathophysiological
association and strengthens the indication for IV in this population. When the
overall results of this study were included in our meta-analysis, the benefits
in reducing events had the same direction and magnitude of effect.
The characteristics mentioned above
could explain the differences found in the stratified analysis of subgroups
according to baseline CV disease. However, through this meta-analysis we cannot
distinguish how many of the subjects recruited for CAD had concomitant HF and
vice versa, or whether the benefit is greater or not in subjects with both
clinical conditions.
To become aware of the magnitude of
the findings on the effectiveness of IV in reducing events in patients with
CVD, the results can be compared with those of traditional pharmacological
treatments such as statins, beta-blockers and angiotensin-converting enzyme
inhibitors (ACE inhibitors). (40) Cardiovascular death decreased with
each treatment in the meta-analyses of the main trials: RR was 24% for statins,
(41) 23% for beta-blockers, (42) and 16% for
ACE inhibitors. (43) Similarly, smoking cessation reduces
the risk of CVD by 39%. (44)
The strengths of this review are the
extensive systematic review of the literature performed and the inclusion of
only randomized clinical trials with low risk of bias. We found low
heterogeneity in the primary and secondary outcomes analyzed, probably due to
the similar trial design, population included, and definition of outcomes.
However, this review has limitations.
We could not assess publication bias due to the low number of studies included
in the meta-analysis. The COVID-19 pandemic had an impact on recruitment,
follow-up, and influenza circulation, which affected the last two large
randomized clinical trials; however, the benefit in reducing major events was
sustained. Few clinical trials have been included, and there is great
variability in the number of subjects included and in their baseline
characteristics. Nevertheless, the reduction in events was in the same
direction, although with a significant difference in the magnitude of the
effect. Finally, the data from the IVVE study have not been published yet in an
indexed journal at the time this analysis was completed and come from the
presentation at a scientific congress; therefore, the results could be modified
or have a different interpretation than the one we have used for this analysis.
CONCLUSION
In this updated meta-analysis of six
randomized controlled clinical trials, influenza vaccination was associated
with a 33% and 36% relative risk reduction of all-cause mortality and
cardiovascular death, respectively, in patients with CVD.
Over the past few decades,
considerable evidence has accumulated about the cardioprotective effects of
influenza vaccination in patients with established cardiovascular disease.
We sought to promote consensus based
on the highest level of evidence about the persistent benefits of influenza
vaccination in patients with CVD by including two new clinical trials in CAD
and HF, confirming the association of vaccination with risk reduction in
subjects with CVD. The present meta-analysis may help health care workers to
strongly recommend influenza vaccination for secondary prevention of cardiovascular
events.
Conflicts of interest
None declared.
(See authors conflicts of interest
forms in the website/ Supplementary material)
1. Sellers SA, Hagan RS, Hayden FG, Fischer WA. The
hidden burden of influenza: A review of the extra-pulmonary complications of
influenza infection. Influenza
Other Respir Viruses 2017;11:372-93. https://doi.org/10.1111/irv.12470
2. Madjid M, Aboshady I, Awan I, Litovsky S, Casscells
SW. Influenza and cardiovascular disease: is there a causal relationship? Tex
Heart Inst J 2004;31:4-13.
3. Warren-Gash C, Smeeth L, Hayward AC. Influenza as a
trigger for acute myocardial infarction or death from cardiovascular disease: a
systematic review. Lancet Infect Dis 2009;9:601‐10.
https://doi.org/10.1016/S1473-3099(09)70233-6
4. Estabragh ZR. Mammas AM.
The cardiovascular manifestations of influenza: A systematic review. Int J Cardiol 2013;167:2397-403. https://doi.org/10.1016/j.ijcard.2013.01.274
5. Naghavi M, Barlas Z, Siadaty S, Naguib S, Madjid M,
Casscells W. Association of influenza vaccination and reduced risk of recurrent
myocardial infarction. Circulation
2000;102:3039-45. https://doi.org/10.1161/01.CIR.102.25.3039
6. Naghavi M, Wyde P, Litovsky S, Madjid M, Akhtar A,
Naguib S, et al. Influenza infection exerts prominent inflammatory and thrombotic
effects on the atherosclerotic plaques of apolipoprotein E-deficient mice.
Circulation 2003;107:762. https://doi.org/10.1161/01.CIR.0000048190.68071.2B
7. Nichol KL, Wuorenma J, von Sternberg T. Benefits of
influenza vaccination for low-, intermediate-, and high-risk senior citizens. Arch Intern Med 1998;158:1769-76. https://doi.org/10.1001/archinte.158.16.1769
8.
Ahmed AE, Nicholson KG, Nguyen-Van-Tam JS. Reduction in mortality associated
with influenza vaccine during 1989-90 epidemic. Lancet 1995;346:591-5. https://doi.org/10.1016/S0140-6736(95)91434-X
9. Caldeira D, Ferreira JJ, Costa J. Influenza
vaccination and prevention of cardiovascular disease mortality. Lancet 2018;391:426-7. https://doi.org/10.1016/S0140-6736(18)30143-0
10. Loomba RS, Aggarwal S, Shah PH, Arora RR.
Influenza Vaccination and Cardiovascular Morbidity and Mortality: Analysis of
292,383 Patients. J Cardiovasc
Pharmacol Ther 2012;17:277-83. https://doi.org/10.1177/1074248411429965
11. Johnstone J, Loeb M, Teo KK. Influenza
vaccination and major adverse vascular events in high-risk patients. Circulation 2012;126:278- 86. https://doi.org/10.1161/CIRCULATIONAHA.111.071100
12. Chothani A, Shah N, Patel NJ, Deshmukh A, Singh V,
Patel N, et al. Vaccination Serology Status and Cardiovascular Mortality: Insight
from NHANES III and Continuous NHANES. Postgrad Med. 2015;127:561-4.
https://doi.org/10.1080/00325481.2015.1064300
13. Grohskopf LA, Sokolow LZ, Broder KR, Walter EB,
Bresee JS, Fry AM, et al. Prevention and control of seasonal influenza with vaccines:
recommendations of the advisory committee on immunization practices - united states, 2017-18 influenza season. MMWR Recomm Rep
2017;66:1–20. https://doi.org/10.15585/mmwr.rr6602a1
14. Davis MM, Taubert K, Benin AL, Brown DW, Mensah
GA, Baddour LM, et al.; American Heart Association; American College of
Cardiology. Influenza vaccination as secondary prevention for cardiovascular
disease: a science advisory from the American Heart Association/American
College of Cardiology. Circulation
2006;114:1549-53. https://doi.org/10.1161/CIRCULATIONAHA.106.178242
15. Piepoli MF, Hoes AW, Agewall S, et al.; ESC
Scientific Document Group. 2016 European Guidelines on cardiovascular disease
prevention in clinical practice: The Sixth Joint Task Force of the European
Society of Cardiology and Other Societies on Cardiovascular Disease Prevention
in Clinical Practice (constituted by representatives of 10 societies and by
invited experts) Developed with the special contribution of the European
Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur
Heart J 2016;37:2315-81. https://doi.org/10.1093/eurheartj/ehw106
16. Liprandi ÁS, Liprandi MIS, Zaidel EJ, Aisenberg
GM, Baranchuk A, Barbosa ECD, et al. Influenza Vaccination for the Prevention
of Cardiovascular Disease in the Americas: Consensus document of the Inter-American
Society of Cardiology and the Word Heart Federation. Glob Heart 2021;1655. https://doi.org/10.5334/gh.1069
17. Yedlapati SH, Khan SU, Talluri S, Lone AN, Khan
MZ, Khan MS, Navar AM, Gulati M, Johnson H, Baum S, Michos ED. Effects of
Influenza Vaccine on Mortality and Cardiovascular Outcomes in Patients With
Cardiovascular Disease: A Systematic Review and Meta-Analysis. J Am Heart Assoc
2021;10:e019636. https://doi.org/10.1161/JAHA.120.019636
18. Rodrigues BS, David C, Costa J, Ferreira JJ, Pinto
FJ, Caldeira D. Influenza vaccination in patients with heart failure: a systematic
review and meta-analysis of observational studies. Heart 2020;106:350-7. https://doi.org/10.1136/heartjnl-2019-315193
19. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses:
the PRISMA statement. J
Clin Epidemiol 2009;62:1006-12. https://doi.org/10.1016/j.
jclinepi.2009.06.005
20. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher
D, Oxman AD, et al. The Cochrane Collaboration’s tool for
assessing risk of bias in randomised trials. BMJ 2011;343:d5928. https://doi.org/10.1136/bmj.d5928
21. Jadad AR, Moore RA, Carroll D, Jenkinson C,
Reynolds DJ, Gavaghan DJ, et al. Assessing the quality
of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1- 12. https://doi.org/10.1016/0197-2456(95)00134-4
22. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003;327:557-60. https://doi.org/10.1136/bmj.327.7414.557
23. Song F, Khan KS, Dinnes J, Sutton AJ. Asymmetric
funnel plots and publication bias in meta-analyses of diagnostic accuracy. Int
J Epidemiol 2002;31:88-9511914301. https://doi.org/10.1093/ije/31.1.88
24. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A.
Rayyan - a web and mobile app for systematic reviews. Systematic Reviews 2016;5:210, https://doi.org/10.1186/s13643-016-0384-4
25. Gurfinkel EP, Leon de la Fuente R, Mendiz O,
Mautner B. Flu vaccination in acute coronary syndromes and planned percutaneous
coronary interventions (FLUVACS) Study. Eur
Heart J 2004;25:25- 31. https://doi.org/10.1016/j.ehj.2003.10.018
26. Ciszewski A, Bilinska ZT, Brydak LB, Kepka C, Kruk
M, Romanowska M, et al. Influenza vaccination in secondary prevention from
coronary ischaemic events in coronary artery disease: FLUCAD study. Eur Heart J
2008;29:1350-8. https://doi.org/10.1093/eurheartj/ehm581
27.
Keshtkar-Jahromi M, Vakili H, Rahnavardi MT. The efficacy of influenza vaccination
in reducing cardiovascular events in patients with coronary artery diseases:
IVCAD study. Clin Microbiol Infect. 2009;15:S395–6.
28. Phrommintikul A, Kuanprasert S, Wongcharoen W,
Kanjanavanit R, Chaiwarith R, Sukonthasarn A. Influenza vaccination reduces
cardiovascular events in patients with acute coronary syndrome. Eur Heart J 2011;32:1730-5. https://doi.org/10.1093/eurheartj/ehr004
29. Fröbert O, Götberg M, Erlinge D, Akhtar Z,
Christiansen EH, MacIntyre CR, et al. Influenza Vaccination After Myocardial
Infarction: A Randomized, Double-Blind, Placebo- Controlled, Multicenter Trial.
Circulation 2021;144:1476-84. https://doi.org/10.1161/CIRCULATIONAHA.121.057042
30. IVVE Loeb M. Influenza vaccine to prevent adverse
vascular events - IVVE. Presented at the American College of Cardiology Annual
Scientific Session (ACC 2022), Washington, DC, April
3, 2022. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2022/04/02/15/50/IVVE. Acceso 1 de Mayo 2022. https://doi.org/10.1055/a-1700-6411
31. McCarthy Z, Xu S, Rahman A, Bragazzi NL,
Corrales-Medina VF, Lee J, et al. Modelling the linkage between influenza
infection and cardiovascular events via thrombosis. Sci Rep 2020;10:14264. https://doi.org/10.1038/s41598-020-70753-0
32. Vardeny O, Solomon SD. Influenza vaccination: a
one-shot deal to reduce cardiovascular events. Eur Heart J 2017;38:334–7. https://doi.org/10.1093/eurheartj/ehw560
33. Fiore AE, Shay DK, Broder K, Iskander JK, Uyeki
TM, Mootrey G, et al. Prevention and control of seasonal influenza with
vaccines: recommendations of the Advisory Committee on Immunization Practices
(ACIP), 2009 [published correction appears in MMWR Recomm Rep. 2009;58:896-7.
34.
Al Rifai M, Khalid U, Misra A, Liu J, Nasir K, Cainzos-Achirica M, et al. Racial and geographic disparities in
influenza vaccination in the U.S. among individuals with atherosclerotic
cardiovascular disease: renewed importance in the setting of COVID-19.Am J Prev
Cardiol 2021;5:100150. https://doi.org/10.1016/j.ajpc.2021.100150
35. Bhatt AS, Liang L, DeVore AD, Fonarow GC, Solomon
SD, Vardeny O, et al. Vaccination trends in patients with heart failure: insights
From Get With The Guidelines-Heart Failure.JACC Heart Fail 2018;6:844–55. https://doi.org/10.1016/j.jchf.2018.04.012
36. Clar C, Oseni Z, Flowers N, Keshtkar-Jahromi M,
Rees K. Influenza vaccines for preventing cardiovascular disease. Cochrane Database Syst Rev 2015:CD005050 https://doi.org/10.1002/14651858.
CD005050.pub3
37.
Villarreal R, Zaidel EJ, Cestari HG, Mele EF, Sosa Liprandi MI, Sosa Liprandi
A. Vacunación antigripal y antineumocócica en pacientes con enfermedad cardiovascular:
proyecto piloto. Rev Argent Cardiol 2016;84:607-9.
38. Wolff AM, Taylor SA, McCabe JF. Using
checklists and reminders in clinical pathways to improve hospital inpatient
care. Med J Aust. 2004;181:428-31. https://doi.org/10.5694/j.1326-5377.2004.
tb06366
39. Christiansen MN, Køber L, Weeke P, Vasan RS,
Jeppesen JL, Smith JG, et al. Age-Specific Trends in Incidence, Mortality, and
Comorbidities of Heart Failure in Denmark, 1995 to 2012. Circulation 2017;135:1214-23. https://doi.org/10.1161/CIRCULATIONAHA.116.025941
40. Michos ED, Udell JA. Am I Getting the Influenza
Shot Too?: Influenza Vaccination as Post-Myocardial
Infarction Care for the Prevention of Cardiovascular Events and Death. Circulation 2021;144:1485- 8. https://doi.org/10.1161/CIRCULATIONAHA.121.057534
41. Yu S, Jin J, Chen Z, Luo X. High-intensity statin
therapy yields better outcomes in acute coronary syndrome patients: a
meta-analysis involving 26,497 patients. Lipids
Health Dis. 2020;19:194. https://doi.org/10.1186/s12944-020-01369-6
42. Freemantle N, Cleland J, Young P, Mason J,
Harrison J. βBlockade after myocardial infarction:
systematic review and meta regression analysis. BMJ
1999;318:1730-7. https://doi.org/10.1136/bmj.318.7200.1730
43. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A,
Murray G, et al. Long-term ACE-inhibitor therapy in patients with heart failure
or left-ventricular dysfunction: a systematic overview of data from individual
patients. ACE-Inhibitor Myocardial Infarction Collaborative
Group.Lancet. 2000;355:1575-81. https://doi.org/10.1016/S0140-6736(00)02212-1
44. Duncan MS, Freiberg MS, Greevy RA Jr, Kundu S,
Vasan RS, Tindle HA. Association of Smoking Cessation With
Subsequent Risk of Cardiovascular Disease. JAMA. 2019;322:642-50. https://doi.org/10.1001/jama.2019.10298
SUPPLEMENTARY MATERIAL
Supplementary material
Table
1. Characteristics of the studies
COVID-19: coronavirus disease-2019,
MACE: major adverse cardiovascular event, MI: myocardial infarction, PCI:
percutaneous coronary intervention.
Supplementary material
Fig.
1. Element of risk of
bias in all the studies included.
Fig.
2. Risk of bias for each study
included.
Fig.
3. Forest plot of the
effect of influenza vaccination versus placebo on all-cause mortality in
patients with heart failure and coronary artery disease.