The protective effect of pneumococcal vaccination on cardiovascular disease in adults: A systematic review and meta-analysis

Open AccessPublished:July 28, 2020DOI:https://doi.org/10.1016/j.ijid.2020.07.038

      Highlights

      • Excessive stimulation of the immune system and subsequent inflammation by pathogens–both bacterial and viral–is thought to lead to cardiovascular events such as myocardial infarction, congestive heart failure and stroke.
      • This meta-analysis showed the 23-valent polysaccharide pneumococcal vaccine (PPV23) provided protection from any cardiovascular event, myocardial infarction and mortality.
      • Protection from the vaccine was seen in individuals of all age groups, but particularly in those aged ≥65 years.
      • PPV23 vaccine for older individuals would not only provide protection against invasive pneumococcal disease and community-acquired pneumonia due to Streptococcus pneumoniae but also prevent cardiovascular events that could lead to early death.

      Abstract

      Background

      Epidemiological studies suggest that there is a link between pneumococcal infection and adverse cardiovascular outcomes such as myocardial infarction. Multiple studies have evaluated the protective effect of the 23-valent polysaccharide pneumococcal vaccination (PPV23), but results have varied. Therefore, a meta-analysis was conducted to summarize available evidence on the impact of PPV23 on cardiovascular disease.

      Methods

      A literature search from January 1946 to September 2019 was conducted across Embase, Medline and Cochrane. All studies were included that evaluated PPV23 compared with a control (placebo, no vaccine or another vaccine) for any cardiovascular events, including: myocardial infarction (MI), heart failure and cerebrovascular events. Risk ratios (RRs) were pooled using random effects models.

      Results

      Eighteen studies were included, with a total of 716,108 participants. Vaccination with PPV23 was associated with decreased risk of any cardiovascular event (RR: 0.91; 95% CI: 0.84−0.99), and MI (RR: 0.88; 95% CI: 0.79−0.98) in all age groups, with a significant effect in those aged ≥65 years, but not in the younger age group. Similarly, PPV23 vaccine was associated with significant risk reduction in all-cause mortality in all ages (RR: 0.78; 95% CI: 0.68−0.88), specifically in those aged ≥65 years (RR: 0.71; 95% CI: 0.60−0.84). A significant risk reduction in cerebrovascular disease was not observed following pneumococcal vaccination.

      Conclusions

      Polysaccharide pneumococcal vaccination decreased the risk for some adverse cardiovascular events, specifically acute MI in the vaccinated population, particularly for those individuals aged ≥65 years. It would be highly beneficial to vaccinate the population who is at greater risk of cardiovascular diseases.

      Keywords

      Introduction

      Cardiovascular disease (CVD) is a leading cause of death in the world, with over 17.9 million people dying from a CVD-related event annually (
      • Naghavi M.
      • Wang H.
      • Lozano R.
      • Davis A.
      • Liang X.
      • Zhou M.
      • et al.
      Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.
      ,
      • World Health Organization
      Cardiovascular Diseases (CVDs).
      ). In fact, an estimated 30% of global deaths in a year are attributed to CVD (
      • World Health Organization
      Cardiovascular Diseases (CVDs).
      ). Although genetic factors greatly contribute to coronary artery disease, so do environmental factors and lifestyle choices. Some common risk factors of CVD include age, diabetes, smoking, obesity, cholesterol, and hypertension (
      • Lieb W.
      • Vasan R.S.
      Genetics of coronary artery disease.
      ,
      • McPherson R.
      • Tybjaerg-Hansen A.
      Genetics of coronary artery disease.
      ,
      • Wong N.D.
      Epidemiological studies of CHD and the evolution of preventive cardiology.
      ).
      Coronary artery disease is essentially inflammatory in nature, and newer evidence shows that inflammation related to respiratory pathogens such as influenza and Streptococcus pneumoniae (S. pneumoniae) can trigger this disease (
      • Corrales-Medina V.F.
      • Madjid M.
      • Musher D.
      Role of acute infection in triggering acute coronary syndromes.
      ,
      • Bova I.Y.
      • Bornstein N.M.
      • Korczyn A.D.
      Acute infection as a risk factor for ischemic stroke.
      ,
      • Brown A.O.
      • Millett E.R.C.
      • Quint J.K.
      • Orihuela C.J.
      Cardiotoxicity during invasive pneumococcal disease.
      ). Macrophages, T cells and neutrophils stimulate the production of cytokines, coagulation factors, oxygen radicals, and vasoactive molecules that increase endothelial damage, cause dysregulation of coagulation cascades, and start the formation of thrombi on plaque, precipitating an acute coronary event or stroke (
      • Corrales-Medina V.F.
      • Madjid M.
      • Musher D.
      Role of acute infection in triggering acute coronary syndromes.
      ). Furthermore, infections increase both sympathetic activity and myocardial oxygen demand, leading to decreased oxygen supply and possible myocardial infarction or heart failure.
      Numerous epidemiological studies show that both influenza and pneumococcal infections exacerbate pre-existing cardiac diseases and trigger new cases of CVD such as myocardial infarction (MI), congestive heart failure (CHF), arrhythmia, stroke, or transient ischemic attack (TIA) (
      • Vardeny O.
      • Solomon S.D.
      Influenza vaccination: a one-shot deal to reduce cardiovascular events.
      ,
      • Warren-Gash C.
      • Smeeth L.
      • Hayward A.C.
      Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review.
      ,
      • Corrales-Medina V.F.
      • Alvarez K.N.
      • Weissfeld L.A.
      • Angus D.C.
      • Chirinos J.A.
      • Chang C.C.
      • et al.
      Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease.
      ,
      • Musher D.M.
      • Rueda A.M.
      • Kaka A.S.
      • Mapara S.A.
      The association between pneumococcal pneumonia and acute cardiac events.
      ). A Cochrane review evaluated eight randomized controlled trials with >12,000 participants and concluded that influenza vaccine significantly reduced cardiovascular mortality (
      • Clar C.
      • Oseni Z.
      • Flowers N.
      • Keshtkar-Jahromi M.
      • Rees K.
      Influenza vaccines for preventing cardiovascular disease.
      ). Unlike the influenza vaccine, the data with respect to pneumococcal vaccination reducing cardiovascular mortality are not as robust, as there are no randomized controlled trials. Moreover, current recommendations for pneumococcal vaccination in patients with CVD are based on expert opinion and retrospective epidemiological studies (
      • Corrales-Medina V.F.
      • Alvarez K.N.
      • Weissfeld L.A.
      • Angus D.C.
      • Chirinos J.A.
      • Chang C.C.
      • et al.
      Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease.
      ,
      • Ciszewski A.
      Cardioprotective effect of influenza and pneumococcal vaccination in patients with cardiovascular diseases.
      ). Thus, this systematic review and meta-analysis were conducted to summarize the protective effect of pneumococcal vaccines on cardiovascular health.

      Methods

      This systematic review and meta-analysis were reported in accordance with PRISMA guidelines (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group T.P.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ).

       Data sources and search strategy

      A search was conducted for publications until September 2019 across the following databases: CENTRAL, EMBASE and Medline using a pre-determined strategy. Relevant keywords and Medical Subject Headings (Mesh) included but were not limited to pneumococcal vaccine AND myocardial infarction OR transient ischemic stroke OR cardiovascular disease OR angina OR heart failure OR coronary heart disease. After compilation of articles from each database and duplicate deletion, titles and abstracts of articles were manually screened for topic relevance. A full text review of articles and their reference lists were then conducted by two independent investigators. Any discordance was resolved through discussion.

       Inclusion and exclusion criteria

      Included studies were randomized controlled trials, cohort studies and case control studies evaluating pneumococcal vaccine and any type of cardiac complication in those aged ≥18 years. Studies were excluded if they: were animal studies, evaluated pneumococcal disease, were non-English, were review papers, had no comparator arm, were an economic evaluation, were clinical guidelines, case reports, case series, and had laboratory diagnosis.

       Data extraction, study verification and quality assessment

      Data were extracted to a standardized table. Data fields included: author, study year, country of origin, study design, percentage of gender, average age, type of vaccination, and outcome. Outcomes included any cardiovascular events (e.g. MI, CHF, TIA, stroke), cardiovascular disease-related hospitalization and mortality. Two authors completed quality assessments for each eligible study following the Newcastle Ottawa guidelines (
      • Wells G.A.
      • Shea B.
      • O’Connell D.
      • Peterson J.
      • Welch V.
      • Losos M.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
      ) and the Cochrane risk of bias tool for RCTs (
      • Higgins J.P.T.
      • Altman D.G.
      • Gøtzsche P.C.
      • Jüni P.
      • Moher D.
      • Oxman A.D.
      • et al.
      The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
      ). Any discrepancy in quality assessments were resolved through discussion until consensus.

       Statistical analysis

      The logarithm of reported estimates and standard errors for corresponding 95% confidence interval for each outcome were calculated. Risk ratios were pooled using the DerSimonian and Liard method with random effect models (
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ,
      • Deeks J.J.
      Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes.
      ). For the primary analysis, the impact of 23-valent polysaccharide pneumococcal vaccine (PPV23) on any cardiovascular event for any age was assessed, and then stratified according to those aged <65 years and ≥65 years, as pneumococcal disease risk increases with age (
      • Bova I.Y.
      • Bornstein N.M.
      • Korczyn A.D.
      Acute infection as a risk factor for ischemic stroke.
      ).
      For secondary analyses, the impact of PPV23 vaccination on specific cardiovascular events such as MI, stroke and mortality (all-cause or CVD-related) was assessed. Publication bias was assessed through funnel plots by comparing standard errors with residual values (
      • Sterne J.A.
      • Egger M.
      Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis.
      ). Statistical significance of heterogeneity was evaluated using Egger’s test and the I2 statistic. A random effects model was also used to account for variability within and between studies (
      • Clar C.
      • Oseni Z.
      • Flowers N.
      • Keshtkar-Jahromi M.
      • Rees K.
      Influenza vaccines for preventing cardiovascular disease.
      ,
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor package.
      ). Mixed effect modeling was used to understand the sources of heterogeneity, such as study design, geographic location, age and sex distribution. All statistical analyses and data visualization were conducted in R Software 3.4.3. using the metafor package (
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor package.
      ).

      Results

       Search strategy, study inclusion and study characteristics

      The literature search generated a total of 660 studies, of which 133 were duplicates, with a further 455 removed for various reasons (Figure 1). A full-text review of the remaining 72 studies led to the exclusion of 53, and the identification of 19 studies for potential inclusion (
      • Chan T.C.
      • Hung I.F.
      • Luk J.K.
      • Shea Y.F.
      • Chan F.H.
      • Woo P.C.
      • et al.
      Prevention of mortality and pneumonia among nursing home older adults by dual pneumococcal and seasonal influenza vaccination during a pandemic caused by novel pandemic influenza A (H1N1).
      ,
      • Chang Y.C.
      • Chou Y.J.
      • Liu J.Y.
      • Yeh T.F.
      • Huang N.
      Additive benefits of pneumococcal and influenza vaccines among elderly persons aged 75 years or older in Taiwan– a representative, population-based comparative study.
      ,
      • Chen L.F.
      • Chen H.P.
      • Huang Y.S.
      • Huang K.Y.
      • Chou P.
      • Lee C.C.
      Pneumococcal pneumonia and the risk of stroke: a population-based follow-up study.
      ,
      • Eurich D.T.
      • Johnstone J.J.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Majumdar S.R.
      Pneumococcal vaccination and risk of acute coronary syndromes in patients with pneumonia: population-based cohort study.
      ,
      • Gilbertson D.T.
      • Guo H.
      • Arneson T.J.
      • Collins A.J.
      The association of pneumococcal vaccination with hospitalization and mortality in hemodialysis patients.
      ,
      • Hedlund J.
      • Christenson B.
      • Lundbergh P.
      • Örtqvist Å
      Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in elderly people: a 1-year follow-up.
      ,
      • Hung I.F.N.
      • Leung A.Y.M.
      • Chu D.W.S.
      • Leung D.
      • Cheung T.
      • Chan C.K.
      • et al.
      Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study.
      ,
      • Jackson L.A.
      • Yu O.
      • Heckbert S.R.
      • Psaty B.M.
      • Malais D.
      • Barlow W.E.
      • et al.
      Vaccine Safety Datalink Study Group
      Influenza vaccination is not associated with a reduction in the risk of recurrent coronary events.
      ,
      • Johnstone J.
      • Loeb M.
      • Teo K.K.
      • Gao P.
      • Dyal L.
      • Liu L.
      • et al.
      Influenza vaccination and major adverse vascular events in high-risk patients.
      ,
      • Lamontagne F.
      • Garant M.P.
      • Carvalho J.C.
      • Lanthier L.
      • Smieja M.
      • Pilon D.
      Pneumococcal vaccination and risk of myocardial infarction.
      ,
      • Meyers D.G.
      • Beahm D.D.
      • Jurisich P.D.
      • Milford C.J.
      • Edlavich S.
      Influenza and pneumococcal vaccinations fail to prevent myocardial infarction.
      ,
      • Ochao-Gondar O.
      • Vila-Corcoles A.
      • Rodriguez-Blanco T.
      • EPIVAC Research Group
      • et al.
      Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
      ,
      • Ren S.
      • Holliday E.
      • Hure A.
      • Peel R.
      • Hancock S.
      • Leigh L.
      • et al.
      Pneumococcal polysaccharide vaccine associated with reduced lengths of stay for cardiovascular events hospital admissions: experience from the Hunter Community Study.
      ,
      • Siriwardena A.N.
      • Gwini S.M.
      • Coupland C.A.
      Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: matched case-control study.
      ,
      • Siriwardena A.N.
      • Asghar Z.
      • Coupland C.C.
      Influenza and pneumococcal vaccination and risk of stroke or transient ischaemic attack-matched case control study.
      ,
      • Tseng H.F.
      • Slezak J.M.
      • Quinn V.P.
      • Sy L.S.
      • SKVD Eeden
      • Jacobsen S.J.
      Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men.
      ,
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • de Diego-Cabanes C.
      • Satue-Gracia E.
      • Vila-Rovira A.
      • et al.
      Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-Year Follow-up.
      ,
      • Zahid M.
      • Singla I.
      • Good C.B.
      • Stone R.A.
      • Kim S.
      • Fine M.
      • et al.
      Associations between pneumococcal vaccination and adverse outcomes in patients with suspected acute coronary syndrome.
      ,
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • Gutierrez-Perez A.
      • Vila-Rovira A.
      • Gomez F.
      • et al.
      Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: the CAPAMIS study, one-year follow-up.
      ). A final review of the studies before extraction eliminated the study by
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • Gutierrez-Perez A.
      • Vila-Rovira A.
      • Gomez F.
      • et al.
      Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: the CAPAMIS study, one-year follow-up.
      as it reported combined results (stroke and acute MI) from the CAPAMIS study. Instead, their publications that delineated acute MI and stroke were separately incorporated (
      • Ochao-Gondar O.
      • Vila-Corcoles A.
      • Rodriguez-Blanco T.
      • EPIVAC Research Group
      • et al.
      Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
      ,
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • de Diego-Cabanes C.
      • Satue-Gracia E.
      • Vila-Rovira A.
      • et al.
      Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-Year Follow-up.
      ).
      Figure 1
      Figure 1Inclusion of studies for the meta-analysis.
      The 18 studies (14 cohort and four case studies) had a total of 716,108 participants, with a mean age ranging from 18 to 86 years (Table 1). The follow-up duration ranged from 4 months to 11 years. Most studies were conducted in North America (eight), followed by Asia (four), Europe (five), and Australia (one). All studies except three evaluated the effect of PPV23 on cardiovascular events: either MI, stroke, CHF, and/or acute coronary event. Seven studies each reported on all-cause mortality data and cause-specific cardiovascular mortality. Based on the Newcastle Ottawa evaluative scale, the overall quality assessments of the included studies ranged from fair to good (Supplemental Appendices A2 and A3).
      Table 1Characteristics of included studies.
      Author, YearStudy designCountryDurationFollow-upStudy population
      Study population includes subjects included in this meta-analysis.
      Mean age (years)% malesExposed/cases (N)
      Exposed/Cases includes subjects exposed to pneumococcal vaccination in cohort and cross-sectional studies and cases for outcome of interest, any CVD, MI or stroke in case-control studies.
      Not-exposed/controls (N)
      Not-exposed/Controls includes subjects not vaccinated with PPV for cohort and cross-sectional studies and controls for outcome other than CVD events in case-control studies.
      Adjusted forOutcomesStudy quality
      1
      • Chan T.C.
      • Hung I.F.
      • Luk J.K.
      • Shea Y.F.
      • Chan F.H.
      • Woo P.C.
      • et al.
      Prevention of mortality and pneumonia among nursing home older adults by dual pneumococcal and seasonal influenza vaccination during a pandemic caused by novel pandemic influenza A (H1N1).
      CohortHong Kong2009–201012 months321863724675Age, gender, smoking status, number of medications and feeding status, CCI, BI (20), nursing home of origin, hospitalization in preceding year, and vaccination status for pneumococcus and seasonal influenza were considered as covariates(1) All-cause mortality (2) CVD mortality6
      2
      • Chang Y.C.
      • Chou Y.J.
      • Liu J.Y.
      • Yeh T.F.
      • Huang N.
      Additive benefits of pneumococcal and influenza vaccines among elderly persons aged 75 years or older in Taiwan– a representative, population-based comparative study.
      CohortTaiwan2008 `4 months16,284804681428142Age, gender, baseline comorbid conditions, and healthcare use during the preceding 12 months(1) Any CVD event (2) Acute MI7
      3
      • Chen L.F.
      • Chen H.P.
      • Huang Y.S.
      • Huang K.Y.
      • Chou P.
      • Lee C.C.
      Pneumococcal pneumonia and the risk of stroke: a population-based follow-up study.
      CohortTaiwan2004–200612 months17,51075+5336117,149Age, gender, comorbidities, geographic region, urbanization level of residence, and socioeconomic status during the first year(1) Ischemic stroke7
      4
      • Eurich D.T.
      • Johnstone J.J.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Majumdar S.R.
      Pneumococcal vaccination and risk of acute coronary syndromes in patients with pneumonia: population-based cohort study.
      CohortCanada2000–20023 months61715952.87255446Propensity Score matched for COPD,DM, CAD, smoking status and CV and other

      medications
      (1) Any CVD event (composite ACS)(2) Acute MI (3) CVD mortality7
      5
      • Gilbertson D.T.
      • Guo H.
      • Arneson T.J.
      • Collins A.J.
      The association of pneumococcal vaccination with hospitalization and mortality in hemodialysis patients.
      CohortUSA2003–20066 months118,53318+5325,09193,442Age, gender, comorbidities(1) All-cause mortality (2) CVD mortality5
      6
      • Hedlund J.
      • Christenson B.
      • Lundbergh P.
      • Örtqvist Å
      Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in elderly people: a 1-year follow-up.
      CohortSweden1998–20001 year259,62776 (median)39.8100,242159,385N/A(1) Any CVD event (cardiac failure)(2) Acute MI (2) All-cause mortality6
      7
      • Hung I.F.N.
      • Leung A.Y.M.
      • Chu D.W.S.
      • Leung D.
      • Cheung T.
      • Chan C.K.
      • et al.
      Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study.
      CohortHong Kong2007–20081.2 years27,2687545.3187525,393Sex and COPD comorbidity(1) Any CVD event (MI, stroke, CHF, IHD) (2) Acute MI(3) Ischemic stroke(4) All-cause mortality6
      8
      • Jackson L.A.
      • Yu O.
      • Heckbert S.R.
      • Psaty B.M.
      • Malais D.
      • Barlow W.E.
      • et al.
      Vaccine Safety Datalink Study Group
      Influenza vaccination is not associated with a reduction in the risk of recurrent coronary events.
      CohortUSA1992–19962.3 years13786467662716Age, gender, influenza vaccination, shock, severe HF during hospitalization, DM, HTN, COPD, asthma, CHF, use of CCB, statins(1) Any CVD event(2) Acute MI (3) CVD mortality8
      9
      • Johnstone J.
      • Loeb M.
      • Teo K.K.
      • Gao P.
      • Dyal L.
      • Liu L.
      • et al.
      Influenza vaccination and major adverse vascular events in high-risk patients.
      Cohort (cross sectional)
      Johnstone et al. (2012) was a questionnaire-based study conducted in the RCT population for another trial called as TRANSCEND. So, was treated as a cross-sectional study in this meta-analysis.
      Canada2003–20076 months22,2636670330318,960Propensity score for pneumococcal vaccination (body mass index, age, sex, ethnicity, education, vitamin use, smoking history, alcohol use, history of influenza vaccination), history of coronary artery disease, diabetes, hypertension, stroke, admission to nursing home use of ASA, beta-blocker, cholesterol lowering drugs, ACE inhibitors(1) Any CVD event (2) Acute MI7
      10
      • Lamontagne F.
      • Garant M.P.
      • Carvalho J.C.
      • Lanthier L.
      • Smieja M.
      • Pilon D.
      Pneumococcal vaccination and risk of myocardial infarction.
      Case controlCanada1997–200310 years (maximum)499558.968.59993996Cases and controls were matched on age, sex and hospitalization index date. Comparisons were adjusted for COPD, CRF, DM, previous S. pneumoniae infection, splenectomy(1) Any CVD event (2) Acute MI6
      11
      • Meyers D.G.
      • Beahm D.D.
      • Jurisich P.D.
      • Milford C.J.
      • Edlavich S.
      Influenza and pneumococcal vaccinations fail to prevent myocardial infarction.
      Case controlUSA2001–20025 years (maximum)5346952.2335199Sex, age, ever smoked, family history of CVD(1) Any CVD event (2) Acute MI6
      12
      • Ochao-Gondar O.
      • Vila-Corcoles A.
      • Rodriguez-Blanco T.
      • EPIVAC Research Group
      • et al.
      Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
      Ochao-Gondar et al. (2014) (AMI) and Vila-Corcoles et al. (2014) (Stroke) reported 3-year data for the CAPAMIS study. They previously published both outcomes–AMI and stroke–together in Vila-Corcoles et al. (2012).
      CohortSpain2008–20113 years27,20471.7 ± 8.644.6898118,223Age, sex, number of outpatient visits in the prior year, influenza vaccination in prior year, history of CAD, chronic heart disease, DM, hypercholesterolemia, smoking, and nursing-home resident(1) Any CVD event (2) Acute MI(3) All-cause mortality(4) CVD mortality8
      13
      • Ren S.
      • Holliday E.
      • Hure A.
      • Peel R.
      • Hancock S.
      • Leigh L.
      • et al.
      Pneumococcal polysaccharide vaccine associated with reduced lengths of stay for cardiovascular events hospital admissions: experience from the Hunter Community Study.
      CohortAustralia2003–201511 years8637245477386Age, smoking, diabetes and alcohol status(1) CVD mortality7
      14
      • Siriwardena A.N.
      • Gwini S.M.
      • Coupland C.A.
      Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: matched case-control study.
      Case controlEngland and Wales2001–200712 months78,70665.638.516,01262,694Asthma, COPD, CAD, stroke or TIA, DM, splenectomy, chronic liver disease, CRF, immunosuppression and HIV, hyperlipidemia, family history of MI, PVD, HTN, smoking, treatment with acetylsalicylic acid, statins, or antihypertensives, and general practice consultations(1) Any CVD event (2) Acute MI7
      15
      • Siriwardena A.N.
      • Asghar Z.
      • Coupland C.C.
      Influenza and pneumococcal vaccination and risk of stroke or transient ischaemic attack-matched case control study.
      Case controlEngland and Wales2001–200912 months53,56865.34826,78426,784Asthma, COPD, or CAD, stroke or TIA, DM, hyperlipidemia, splenectomy, chronic liver disease, CRF, immunosuppression, HIV/ AIDS, family history of AMI, PVD, HTN, smoking status, treatment with acetylsalicylic acid or statins, or antihypertensives, GP consultations, BMI(1) Any CVD event (2) Ischemic stroke8
      16
      • Tseng H.F.
      • Slezak J.M.
      • Quinn V.P.
      • Sy L.S.
      • SKVD Eeden
      • Jacobsen S.J.
      Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men.
      CohortUSA2002–20074.7 years84,17058.4 ± 7.110036,30947,861Propensity score adjustment for pneumococcal vaccination. Age, region, race, ethnicity, income, physical inactivity, education, history of MI or stroke, or PAD, cholesterol, HTN, DM, BMI, influenza vaccination, alcohol consumption, outpatient visits(1) Acute MI(2) Ischemic Stroke(3) Any CVD event7
      17
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • de Diego-Cabanes C.
      • Satue-Gracia E.
      • Vila-Rovira A.
      • et al.
      Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-Year Follow-up.
      Ochao-Gondar et al. (2014) (AMI) and Vila-Corcoles et al. (2014) (Stroke) reported 3-year data for the CAPAMIS study. They previously published both outcomes–AMI and stroke–together in Vila-Corcoles et al. (2012).
      CohortSpain2008–20113 years27,20471.7 ± 8.644.6898118,223Adjusted for age, sex, number of outpatient visits in prior year, influenza vaccination in prior year, history of CAD, chronic heart disease, DM, hypercholesterolemia, smoking, and nursing-home resident(1) Any CVD event (2) Ischemic stroke(3) All-cause mortality(4) CVD (stroke) mortality8
      18
      • Zahid M.
      • Singla I.
      • Good C.B.
      • Stone R.A.
      • Kim S.
      • Fine M.
      • et al.
      Associations between pneumococcal vaccination and adverse outcomes in patients with suspected acute coronary syndrome.
      CohortUSA2001–20066 months14366797.7937499Propensity score adjustment for pneumococcal vaccination. Adjust for: influenza vaccination only, pneumococcal and influenza vaccinations,age (per year),SBP < 90 mmHg,pulmonary edema on admission,hemoglobin<11.5 gm/dL, leftventricular ejection fraction<35%, smoking (past/current), increased troponin, DM, statins, and missing data(1) Any CVD event (2) Acute MI (3) All-cause mortality8
      Abbreviations: ACE-Acetylsalicylic acid; ACS-acute coronary syndrome; AMI-acute myocardial infarction; ASA- Acetylsalicylic acid; BI(20)-Barthel Index 20; BMI-body mass index; CAD-coronary artery disease; CCB-calcium channel blockers; CCI-Charlson Comorbidity Index; CHF-congestive heart failure; CRF-chronic renal failure; CVD-cardiovascular disease; COPD-chronic obstructive pulmonary disease; DM-diabetes mellitus; HIV/ AIDS- human immunodeficiency virus/ acquired immunodeficiency syndrome; HTN-hypertension; TIA-transient ischemic attack; MI-myocardial infarction; PAD- Peripheral artery disease; PVD-peripheral vascular disease; PPV- 23-valent pneumococcal polysaccharide vaccine; SBP- Systolic Blood Pressure.
      a Study population includes subjects included in this meta-analysis.
      b Exposed/Cases includes subjects exposed to pneumococcal vaccination in cohort and cross-sectional studies and cases for outcome of interest, any CVD, MI or stroke in case-control studies.
      c Not-exposed/Controls includes subjects not vaccinated with PPV for cohort and cross-sectional studies and controls for outcome other than CVD events in case-control studies.
      d
      • Johnstone J.
      • Loeb M.
      • Teo K.K.
      • Gao P.
      • Dyal L.
      • Liu L.
      • et al.
      Influenza vaccination and major adverse vascular events in high-risk patients.
      was a questionnaire-based study conducted in the RCT population for another trial called as TRANSCEND. So, was treated as a cross-sectional study in this meta-analysis.
      e
      • Ochao-Gondar O.
      • Vila-Corcoles A.
      • Rodriguez-Blanco T.
      • EPIVAC Research Group
      • et al.
      Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
      (AMI) and
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • de Diego-Cabanes C.
      • Satue-Gracia E.
      • Vila-Rovira A.
      • et al.
      Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-Year Follow-up.
      (Stroke) reported 3-year data for the CAPAMIS study. They previously published both outcomes–AMI and stroke–together in
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • Gutierrez-Perez A.
      • Vila-Rovira A.
      • Gomez F.
      • et al.
      Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: the CAPAMIS study, one-year follow-up.
      .

       Effect of pneumococcal vaccination on any cardiovascular disease-related event

      A total of 15 unique studies looked at PPV23 and its effects on any CVD event (Figure 2). When evaluating individuals across all ages, pneumococcal vaccination was significantly associated with decreased risk of any CVD event, (RR: 0.91; 95% CI: 0.84−0.99; I2 = 74.64%; p < 0.0001). Removal of outliers improved the estimates, while direction remained the same. When stratified by age: pneumococcal vaccine significantly decreased the risk of CVD events (RR: 0.94; 95% CI: 0.89−0.99; I2 = 26.2%; p = 0.19) for individuals aged ≥65 years, while no significant change was seen in those aged <65 years (RR: 1.08; 95% CI: 0.88–1.33; I2 = 86.8%; p < 0.0001).
      Figure 2
      Figure 2Any cardiovascular event and pneumococcal vaccination.

       Effect of pneumococcal vaccination on myocardial infarction

      A total of 12 studies–nine cohort and three case-control–included MI as their main outcome (Figure 3) (
      • Chang Y.C.
      • Chou Y.J.
      • Liu J.Y.
      • Yeh T.F.
      • Huang N.
      Additive benefits of pneumococcal and influenza vaccines among elderly persons aged 75 years or older in Taiwan– a representative, population-based comparative study.
      ,
      • Eurich D.T.
      • Johnstone J.J.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Majumdar S.R.
      Pneumococcal vaccination and risk of acute coronary syndromes in patients with pneumonia: population-based cohort study.
      ,
      • Hedlund J.
      • Christenson B.
      • Lundbergh P.
      • Örtqvist Å
      Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in elderly people: a 1-year follow-up.
      ,
      • Hung I.F.N.
      • Leung A.Y.M.
      • Chu D.W.S.
      • Leung D.
      • Cheung T.
      • Chan C.K.
      • et al.
      Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study.
      ,
      • Jackson L.A.
      • Yu O.
      • Heckbert S.R.
      • Psaty B.M.
      • Malais D.
      • Barlow W.E.
      • et al.
      Vaccine Safety Datalink Study Group
      Influenza vaccination is not associated with a reduction in the risk of recurrent coronary events.
      ,
      • Johnstone J.
      • Loeb M.
      • Teo K.K.
      • Gao P.
      • Dyal L.
      • Liu L.
      • et al.
      Influenza vaccination and major adverse vascular events in high-risk patients.
      ,
      • Lamontagne F.
      • Garant M.P.
      • Carvalho J.C.
      • Lanthier L.
      • Smieja M.
      • Pilon D.
      Pneumococcal vaccination and risk of myocardial infarction.
      ,
      • Meyers D.G.
      • Beahm D.D.
      • Jurisich P.D.
      • Milford C.J.
      • Edlavich S.
      Influenza and pneumococcal vaccinations fail to prevent myocardial infarction.
      ,
      • Ochao-Gondar O.
      • Vila-Corcoles A.
      • Rodriguez-Blanco T.
      • EPIVAC Research Group
      • et al.
      Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
      ,
      • Siriwardena A.N.
      • Gwini S.M.
      • Coupland C.A.
      Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: matched case-control study.
      ,
      • Tseng H.F.
      • Slezak J.M.
      • Quinn V.P.
      • Sy L.S.
      • SKVD Eeden
      • Jacobsen S.J.
      Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men.
      ,
      • Zahid M.
      • Singla I.
      • Good C.B.
      • Stone R.A.
      • Kim S.
      • Fine M.
      • et al.
      Associations between pneumococcal vaccination and adverse outcomes in patients with suspected acute coronary syndrome.
      ). A modest risk reduction in MI was seen following pneumococcal vaccination in the population (RR: 0.88; 95% CI: 0.79−0.98; I2 = 75.4%; p < 0.0001). Age stratification identified a significant effect in those aged ≥65 years (RR: 0.93; 95% CI: 0.88−0.99; I2 = 31.0%; p = 0.20), with no difference for those aged <65 years (RR: 1.06; 95% CI: 0.79–1.42; I2 = 89.4%; p < 0.0001).
      Figure 3
      Figure 3Myocardial infarction and pneumococcal vaccination.

       Effect of pneumococcal vaccination on cerebrovascular disease

      The impact of PPV23 on cerebrovascular disease (stroke/TIA) was evaluated in five studies: four cohort studies and one case control (Figure 4) (
      • Chen L.F.
      • Chen H.P.
      • Huang Y.S.
      • Huang K.Y.
      • Chou P.
      • Lee C.C.
      Pneumococcal pneumonia and the risk of stroke: a population-based follow-up study.
      ,
      • Hung I.F.N.
      • Leung A.Y.M.
      • Chu D.W.S.
      • Leung D.
      • Cheung T.
      • Chan C.K.
      • et al.
      Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study.
      ,
      • Siriwardena A.N.
      • Asghar Z.
      • Coupland C.C.
      Influenza and pneumococcal vaccination and risk of stroke or transient ischaemic attack-matched case control study.
      ,
      • Tseng H.F.
      • Slezak J.M.
      • Quinn V.P.
      • Sy L.S.
      • SKVD Eeden
      • Jacobsen S.J.
      Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men.
      ,
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • de Diego-Cabanes C.
      • Satue-Gracia E.
      • Vila-Rovira A.
      • et al.
      Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-Year Follow-up.
      ). A significant risk reduction in cerebrovascular disease following pneumococcal vaccination was not observed (RR: 0.96; 95% CI: 0.83–1.10; I2 = 74.3%; p < 0.001).
      Figure 4
      Figure 4Cerebrovascular event and pneumococcal vaccination.

       Effect of pneumococcal vaccination on all- cause and cardiovascular disease-related mortality

      Seven studies assessed the impact of pneumococcal vaccine on all-cause mortality and a significant risk reduction in all-cause mortality was observed for pneumococcal vaccination compared with controls (RR: 0.78: 95% CI: 0.68−0.88; I2 = 70.4%; p < 0.001) (Figure 5) (
      • Chan T.C.
      • Hung I.F.
      • Luk J.K.
      • Shea Y.F.
      • Chan F.H.
      • Woo P.C.
      • et al.
      Prevention of mortality and pneumonia among nursing home older adults by dual pneumococcal and seasonal influenza vaccination during a pandemic caused by novel pandemic influenza A (H1N1).
      ,
      • Gilbertson D.T.
      • Guo H.
      • Arneson T.J.
      • Collins A.J.
      The association of pneumococcal vaccination with hospitalization and mortality in hemodialysis patients.
      ,
      • Hedlund J.
      • Christenson B.
      • Lundbergh P.
      • Örtqvist Å
      Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in elderly people: a 1-year follow-up.
      ,
      • Hung I.F.N.
      • Leung A.Y.M.
      • Chu D.W.S.
      • Leung D.
      • Cheung T.
      • Chan C.K.
      • et al.
      Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study.
      ,
      • Ochao-Gondar O.
      • Vila-Corcoles A.
      • Rodriguez-Blanco T.
      • EPIVAC Research Group
      • et al.
      Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
      ,
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • de Diego-Cabanes C.
      • Satue-Gracia E.
      • Vila-Rovira A.
      • et al.
      Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-Year Follow-up.
      ,
      • Zahid M.
      • Singla I.
      • Good C.B.
      • Stone R.A.
      • Kim S.
      • Fine M.
      • et al.
      Associations between pneumococcal vaccination and adverse outcomes in patients with suspected acute coronary syndrome.
      ). Cause-specific mortality, in terms of cardiovascular death, was evaluated in seven studies and once again a reduction in risk was attributed to vaccination with PPV23 (RR: 0.92: 95% CI: 0.86−0.98; I2 = 0.0%; p = 0.57) (Figure 5) (
      • Chan T.C.
      • Hung I.F.
      • Luk J.K.
      • Shea Y.F.
      • Chan F.H.
      • Woo P.C.
      • et al.
      Prevention of mortality and pneumonia among nursing home older adults by dual pneumococcal and seasonal influenza vaccination during a pandemic caused by novel pandemic influenza A (H1N1).
      ,
      • Eurich D.T.
      • Johnstone J.J.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Majumdar S.R.
      Pneumococcal vaccination and risk of acute coronary syndromes in patients with pneumonia: population-based cohort study.
      ,
      • Gilbertson D.T.
      • Guo H.
      • Arneson T.J.
      • Collins A.J.
      The association of pneumococcal vaccination with hospitalization and mortality in hemodialysis patients.
      ,
      • Jackson L.A.
      • Yu O.
      • Heckbert S.R.
      • Psaty B.M.
      • Malais D.
      • Barlow W.E.
      • et al.
      Vaccine Safety Datalink Study Group
      Influenza vaccination is not associated with a reduction in the risk of recurrent coronary events.
      ,
      • Ochao-Gondar O.
      • Vila-Corcoles A.
      • Rodriguez-Blanco T.
      • EPIVAC Research Group
      • et al.
      Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
      ,
      • Ren S.
      • Holliday E.
      • Hure A.
      • Peel R.
      • Hancock S.
      • Leigh L.
      • et al.
      Pneumococcal polysaccharide vaccine associated with reduced lengths of stay for cardiovascular events hospital admissions: experience from the Hunter Community Study.
      ,
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • de Diego-Cabanes C.
      • Satue-Gracia E.
      • Vila-Rovira A.
      • et al.
      Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-Year Follow-up.
      ).
      Figure 5
      Figure 5Mortality and pneumococcal vaccination.
      Sensitivity analyses of the main end points showed that the results remained robust after the removal of outliers (Supplement A4). No publication bias was found, and sources of heterogeneity were mainly associated with age and follow-up duration in all analyses (Supplement A5–A10).

      Discussion

      This meta-analysis identified the protective effects of vaccination with PPV23 for any cardiovascular-related event across all ages. This effect was most pronounced in individuals aged ≥65 years. In analyzing specific cardiac events, it was found that PPV23 was protective for myocardial infarction for adults aged ≥65 years. The pneumococcal polysaccharide vaccine was found to convey further protective benefits against all-cause and cardiovascular-related mortality. However, the PPV23 vaccine was not found to be helpful for prevention of stroke, although that may have been due to the low number of studies for this outcome.
      The results of this study have been corroborated by two previously published meta-analyses; however, both these studies were smaller in scope. Ren et al. combined data from eight observational studies, consisting of 230,426 participants, and showed a lower risk of acute coronary events for individuals aged ≥65 years (
      • Ren S.
      • Newby D.
      • Li S.C.
      • Walkom E.
      • Miller P.
      • Hure A.
      • et al.
      Effect of the adult pneumococcal polysaccharide vaccine on cardiovascular disease: a systematic review and meta-analysis.
      ). Parallel to the current study, they did not find a significant reduction in stroke following pneumococcal vaccination. In another review, Vlachopoulos et al. included data from 13 studies with 332,267 participants (
      • Vlachopoulos C.V.
      • Terentes-Printzios D.G.
      • Aznaouridis K.A.
      • Pietri P.G.
      • Stefanadis C.I.
      Association between pneumococcal vaccination and cardiovascular outcomes: a systematic review and meta-analysis of cohort studies.
      ). They identified that individuals who received PPV23 vaccine had a 14% lower risk of total cardiovascular events and 8% for cardiovascular mortality compared with those who had not been immunized.
      The current review observed a wide variation in the original estimates, which may be attributed to the included studies having large differences in the age of the underlying population, inadequate sample size, exclusive sub-populations (like men or hemodialysis patients), and variable follow-up periods. For example, MI risk reduction was found to be significantly higher following pneumococcal vaccination in studies with shorter-term follow-up (3–6 months only) (
      • Chang Y.C.
      • Chou Y.J.
      • Liu J.Y.
      • Yeh T.F.
      • Huang N.
      Additive benefits of pneumococcal and influenza vaccines among elderly persons aged 75 years or older in Taiwan– a representative, population-based comparative study.
      ,
      • Eurich D.T.
      • Johnstone J.J.
      • Minhas-Sandhu J.K.
      • Marrie T.J.
      • Majumdar S.R.
      Pneumococcal vaccination and risk of acute coronary syndromes in patients with pneumonia: population-based cohort study.
      ,
      • Zahid M.
      • Singla I.
      • Good C.B.
      • Stone R.A.
      • Kim S.
      • Fine M.
      • et al.
      Associations between pneumococcal vaccination and adverse outcomes in patients with suspected acute coronary syndrome.
      ). For example, Ochoa-Gondar et al. reported significant risk reduction from MI at 1 year but the protective effect attenuated over time (
      • Ochao-Gondar O.
      • Vila-Corcoles A.
      • Rodriguez-Blanco T.
      • EPIVAC Research Group
      • et al.
      Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
      ).
      Although the individual studies evaluating vaccine benefit for individuals aged 18–64 years adjusted for many confounders, the controls were generally healthier and did not have major risk factors like diabetes mellitus, high blood pressure, congestive heart failure, and smoking, in comparison with the vaccinated group; this led to residual confounding and the possibility of missing an effect when it may have been present. Further, a number of studies included patients who had received PPV23 up to 5 years prior to study commencement and, therefore, the effect of the vaccine in the younger individuals may have been missed. As a result, none of the meta-analyses, including the current one, found vaccine benefit when the results were stratified for those aged <65 years, for any of the outcomes, be it any cardiovascular event, MI, stroke, or mortality.
      Low numbers and an absence of specific-event reporting across the individual studies included in the current meta-analysis also led to the inability to analyze the impact of PPV23 on the prevention of new or worsening heart failure or arrhythmias. It would have been interesting to see this effect, as previous studies have shown patients with pneumococcal disease, including pneumonia, are not only at risk for an MI, but also serious arrhythmia, or new/worsening CHF. For example, Musher et al. studied cardiovascular events, at the time of hospital admission, in 170 patients hospitalized with pneumococcal pneumonia (
      • Musher D.M.
      • Rueda A.M.
      • Kaka A.S.
      • Mapara S.A.
      The association between pneumococcal pneumonia and acute cardiac events.
      ). The incidence of new-onset or worsening CHF and arrhythmias (atrial flutter, atrial fibrillation and ventricular tachycardia, with the exclusion of terminal arrhythmias) was 14% and 5.8%, respectively (
      • Musher D.M.
      • Rueda A.M.
      • Kaka A.S.
      • Mapara S.A.
      The association between pneumococcal pneumonia and acute cardiac events.
      ). Perry et al. reported similar findings to Musher in their cohort of recently hospitalized patients with pneumonia, with the incidence of new or repeat congestive heart failure being 19.2% and 6.4% for cardiac arrhythmias (
      • Perry T.W.
      • Pugh M.J.
      • Waterer G.W.
      • Nakashima B.
      • Orihuela C.J.
      • Copeland L.A.
      • et al.
      Incidence of cardiovascular events after hospital admission for pneumonia.
      ).
      The current study found significant risk reduction in all-cause mortality and cardiovascular-related mortality. While the results were robust for those aged ≥65 years with respect to all-cause mortality, significance was not observed in older adults with respect to cause-specific mortality, with three of the four studies showing non-significance. However, this finding may be related to the three studies having long follow-up periods of 3–11 years, whereby the vaccine’s protective effect diminished with time (
      • Ochao-Gondar O.
      • Vila-Corcoles A.
      • Rodriguez-Blanco T.
      • EPIVAC Research Group
      • et al.
      Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
      ,
      • Ren S.
      • Holliday E.
      • Hure A.
      • Peel R.
      • Hancock S.
      • Leigh L.
      • et al.
      Pneumococcal polysaccharide vaccine associated with reduced lengths of stay for cardiovascular events hospital admissions: experience from the Hunter Community Study.
      ,
      • Vila-Corcoles A.
      • Ochoa-Gondar O.
      • Rodriguez-Blanco T.
      • de Diego-Cabanes C.
      • Satue-Gracia E.
      • Vila-Rovira A.
      • et al.
      Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-Year Follow-up.
      ). As mortality was not evaluated in those aged 18–64 years, there is a need to prospectively study the vaccine’s effect in younger cohorts, particularly in the presence of chronic underlying illness.
      Since all included studies were observational in nature, the results of this meta-analysis should be interpreted with caution, due to the inherent bias and confounders that could affect the study outcome. In addition, it found that the overall quality of evidence was fair. Studies had wide durations of follow-up, ranging from 90 days to several years, while the definitions of the various cardiovascular outcomes varied from one study to another, posing a risk for misclassification bias. Finally, patients who were given PPV23 may have had more comorbidities and a higher underlying cardiac risk than those who were not offered the vaccine, suggesting a possible underestimation of the effect of PPV23, although most studies adjusted for potential confounders or used propensity score matching. The current meta-analysis included all studies that evaluated the effect of PPV23 vaccine on cardiovascular events. This included studies that reported on people receiving both PPV23 and influenza vaccines at the same time, providing they adjusted for influenza in their analyses. As such, the results should be interpreted with caution, as the effect may have been related to influenza or a combination of both vaccines, rather than only PPV23.

      Conclusions and implications

      Cardiovascular disease remains a major cause of morbidity and mortality, and prevention is key to decreasing this burden. Newer evidence has shown coronary artery disease to be inflammatory in nature and since respiratory pathogens, such as influenza and S. pneumoniae, also activate macrophages, lymphocytes and cytokines, it is plausible that they could trigger myocardial infarction, heart failure and stroke (
      • Corrales-Medina V.F.
      • Madjid M.
      • Musher D.
      Role of acute infection in triggering acute coronary syndromes.
      ,
      • Bova I.Y.
      • Bornstein N.M.
      • Korczyn A.D.
      Acute infection as a risk factor for ischemic stroke.
      ,
      • Brown A.O.
      • Millett E.R.C.
      • Quint J.K.
      • Orihuela C.J.
      Cardiotoxicity during invasive pneumococcal disease.
      ,
      • Vardeny O.
      • Solomon S.D.
      Influenza vaccination: a one-shot deal to reduce cardiovascular events.
      ). This study found pneumococcal vaccination to be associated with a significant risk reduction for cardiovascular diseases in those aged ≥65 years. These individuals would benefit from receiving the pneumococcal vaccination which, at present, has a very low vaccination rate.

      Author contributions

      FM conceived and designed the study, interpreted the data, wrote the first manuscript and subsequent drafts; AZ conducted the literature research; AZ, EG, KB acquired and validated the data; AZ, and KP performed data analysis; NV conducted the literature search, data extraction, data validation, data analyses and interpreted the data. All authors critically revised the article for important intellectual content, and approved the final version submitted.

      Conflict of interest

      None.

      Funding

      None.

      Appendix A. Supplementary data

      References

        • Bova I.Y.
        • Bornstein N.M.
        • Korczyn A.D.
        Acute infection as a risk factor for ischemic stroke.
        Stroke. 1996; 27: 2204-2206
        • Brown A.O.
        • Millett E.R.C.
        • Quint J.K.
        • Orihuela C.J.
        Cardiotoxicity during invasive pneumococcal disease.
        Am J Respir Crit Care Med. 2015; 191: 739-745https://doi.org/10.1164/rccm.201411-1951PP
        • Chan T.C.
        • Hung I.F.
        • Luk J.K.
        • Shea Y.F.
        • Chan F.H.
        • Woo P.C.
        • et al.
        Prevention of mortality and pneumonia among nursing home older adults by dual pneumococcal and seasonal influenza vaccination during a pandemic caused by novel pandemic influenza A (H1N1).
        J Am Med Dir Assoc. 2012; 13: 698-703https://doi.org/10.1016/j.jamda.2012.05.009
        • Chang Y.C.
        • Chou Y.J.
        • Liu J.Y.
        • Yeh T.F.
        • Huang N.
        Additive benefits of pneumococcal and influenza vaccines among elderly persons aged 75 years or older in Taiwan– a representative, population-based comparative study.
        J Infect. 2012; 65: 231-238
        • Chen L.F.
        • Chen H.P.
        • Huang Y.S.
        • Huang K.Y.
        • Chou P.
        • Lee C.C.
        Pneumococcal pneumonia and the risk of stroke: a population-based follow-up study.
        PloS One. 2012; 7e51452https://doi.org/10.1371/journal.pone.0051452
        • Ciszewski A.
        Cardioprotective effect of influenza and pneumococcal vaccination in patients with cardiovascular diseases.
        Vaccine. 2018; 36: 202-206
        • Clar C.
        • Oseni Z.
        • Flowers N.
        • Keshtkar-Jahromi M.
        • Rees K.
        Influenza vaccines for preventing cardiovascular disease.
        Cochrane Database Syst Rev. 2015; (Art. No. CD005050)
        • Corrales-Medina V.F.
        • Madjid M.
        • Musher D.
        Role of acute infection in triggering acute coronary syndromes.
        Lancet Infect Dis. 2010; 10: 83-92
        • Corrales-Medina V.F.
        • Alvarez K.N.
        • Weissfeld L.A.
        • Angus D.C.
        • Chirinos J.A.
        • Chang C.C.
        • et al.
        Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease.
        JAMA. 2015; 313: 264-274
        • Deeks J.J.
        Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes.
        Stat Med. 2002; 21: 1575-1600
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Eurich D.T.
        • Johnstone J.J.
        • Minhas-Sandhu J.K.
        • Marrie T.J.
        • Majumdar S.R.
        Pneumococcal vaccination and risk of acute coronary syndromes in patients with pneumonia: population-based cohort study.
        Heart. 2012; 98: 1072-1077https://doi.org/10.1136/heartjnl-2012-301743
        • Gilbertson D.T.
        • Guo H.
        • Arneson T.J.
        • Collins A.J.
        The association of pneumococcal vaccination with hospitalization and mortality in hemodialysis patients.
        Nephrol Dial Transplant. 2011; 26: 2934-2939https://doi.org/10.1093/ndt/gfq853
        • Hedlund J.
        • Christenson B.
        • Lundbergh P.
        • Örtqvist Å
        Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in elderly people: a 1-year follow-up.
        Vaccine. 2003; 21: 3906-3911https://doi.org/10.1016/S0264-410X(03)00296-2
        • Higgins J.P.T.
        • Altman D.G.
        • Gøtzsche P.C.
        • Jüni P.
        • Moher D.
        • Oxman A.D.
        • et al.
        The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343 (Cochrane Bias Methods Group; Cochrane Statistical Methods Group): d5928https://doi.org/10.1136/bmj.d5928
        • Hung I.F.N.
        • Leung A.Y.M.
        • Chu D.W.S.
        • Leung D.
        • Cheung T.
        • Chan C.K.
        • et al.
        Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study.
        Clin Infect Dis. 2010; 51: 1007-1016https://doi.org/10.1086/656587
        • Jackson L.A.
        • Yu O.
        • Heckbert S.R.
        • Psaty B.M.
        • Malais D.
        • Barlow W.E.
        • et al.
        • Vaccine Safety Datalink Study Group
        Influenza vaccination is not associated with a reduction in the risk of recurrent coronary events.
        Am J Epidemiol. 2002; 156: 634-640https://doi.org/10.1093/aje/kwf073
        • Johnstone J.
        • Loeb M.
        • Teo K.K.
        • Gao P.
        • Dyal L.
        • Liu L.
        • et al.
        Influenza vaccination and major adverse vascular events in high-risk patients.
        Circulation. 2012; 126 (Ongoing Telmisartan Alone and in Combination With Ramipril Global EndPoint Trial (ONTARGET) Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) Investigators): 278-286https://doi.org/10.1161/CIRCULATIONAHA.111.071100
        • Lamontagne F.
        • Garant M.P.
        • Carvalho J.C.
        • Lanthier L.
        • Smieja M.
        • Pilon D.
        Pneumococcal vaccination and risk of myocardial infarction.
        CMAJ. 2008; 179: 773-777
        • Lieb W.
        • Vasan R.S.
        Genetics of coronary artery disease.
        Circulation. 2013; 128: 1131-1138
        • McPherson R.
        • Tybjaerg-Hansen A.
        Genetics of coronary artery disease.
        Circ Res. 2016; 118: 564-578https://doi.org/10.1161/CIRCRESAHA.115.306566
        • Meyers D.G.
        • Beahm D.D.
        • Jurisich P.D.
        • Milford C.J.
        • Edlavich S.
        Influenza and pneumococcal vaccinations fail to prevent myocardial infarction.
        Heart Drug. 2004; 4: 96-100
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • Group T.P.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLOS Med. 2009; 6e1000097https://doi.org/10.1371/journal.pmed.1000097
        • Musher D.M.
        • Rueda A.M.
        • Kaka A.S.
        • Mapara S.A.
        The association between pneumococcal pneumonia and acute cardiac events.
        Clin Infect Dis. 2007; 45: 158-165
        • Naghavi M.
        • Wang H.
        • Lozano R.
        • Davis A.
        • Liang X.
        • Zhou M.
        • et al.
        Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.
        Lancet. 2015; 385: 117-171
        • Ochao-Gondar O.
        • Vila-Corcoles A.
        • Rodriguez-Blanco T.
        • EPIVAC Research Group
        • et al.
        Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up.
        Vaccine. 2014; 32: 252-257
        • Perry T.W.
        • Pugh M.J.
        • Waterer G.W.
        • Nakashima B.
        • Orihuela C.J.
        • Copeland L.A.
        • et al.
        Incidence of cardiovascular events after hospital admission for pneumonia.
        Am J Med. 2011; 124 (PMID: 21396508; PMCID: PMC3061467): 244-251https://doi.org/10.1016/j.amjmed.2010.11.014
        • Ren S.
        • Newby D.
        • Li S.C.
        • Walkom E.
        • Miller P.
        • Hure A.
        • et al.
        Effect of the adult pneumococcal polysaccharide vaccine on cardiovascular disease: a systematic review and meta-analysis.
        Open Heart. 2015; 2 (PMID: 26196020; PMCID: PMC4488890)e000247https://doi.org/10.1136/openhrt-2015-000247
        • Ren S.
        • Holliday E.
        • Hure A.
        • Peel R.
        • Hancock S.
        • Leigh L.
        • et al.
        Pneumococcal polysaccharide vaccine associated with reduced lengths of stay for cardiovascular events hospital admissions: experience from the Hunter Community Study.
        Vaccine. 2018; 36: 7520-7524https://doi.org/10.1016/j.vaccine.2018.10.064
        • Siriwardena A.N.
        • Gwini S.M.
        • Coupland C.A.
        Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: matched case-control study.
        CMAJ. 2010; 182: 1617-1623
        • Siriwardena A.N.
        • Asghar Z.
        • Coupland C.C.
        Influenza and pneumococcal vaccination and risk of stroke or transient ischaemic attack-matched case control study.
        Vaccine. 2014; 32: 1354-1361
        • Sterne J.A.
        • Egger M.
        Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis.
        J Clin Epidemiol. 2001; 54: 1046-1055
        • Tseng H.F.
        • Slezak J.M.
        • Quinn V.P.
        • Sy L.S.
        • SKVD Eeden
        • Jacobsen S.J.
        Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men.
        JAMA. 2010; 303: 1699-1706https://doi.org/10.1001/jama.2010.529
        • Vardeny O.
        • Solomon S.D.
        Influenza vaccination: a one-shot deal to reduce cardiovascular events.
        Eur Heart J. 2017; 38: 334-337https://doi.org/10.1093/eurheartj/ehw560
        • Viechtbauer W.
        Conducting meta-analyses in R with the metafor package.
        J Stat Software. 2010; 36: 1-48
        • Vila-Corcoles A.
        • Ochoa-Gondar O.
        • Rodriguez-Blanco T.
        • Gutierrez-Perez A.
        • Vila-Rovira A.
        • Gomez F.
        • et al.
        Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: the CAPAMIS study, one-year follow-up.
        BMC Public Health. 2012; 12: 222
        • Vila-Corcoles A.
        • Ochoa-Gondar O.
        • Rodriguez-Blanco T.
        • de Diego-Cabanes C.
        • Satue-Gracia E.
        • Vila-Rovira A.
        • et al.
        Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-Year Follow-up.
        J Stroke Cerebrovasc Dis. 2014; 23: 1577-1584
        • Vlachopoulos C.V.
        • Terentes-Printzios D.G.
        • Aznaouridis K.A.
        • Pietri P.G.
        • Stefanadis C.I.
        Association between pneumococcal vaccination and cardiovascular outcomes: a systematic review and meta-analysis of cohort studies.
        Eur J Prev Cardiol. 2015; 22 (Epub 2014 Sep 24): 1185-1199https://doi.org/10.1177/2047487314549512
        • Warren-Gash C.
        • Smeeth L.
        • Hayward A.C.
        Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review.
        Lancet Infect Dis. 2009; 9: 601-610
        • Wells G.A.
        • Shea B.
        • O’Connell D.
        • Peterson J.
        • Welch V.
        • Losos M.
        • et al.
        The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
        OHRI. 2011;
        • Wong N.D.
        Epidemiological studies of CHD and the evolution of preventive cardiology.
        Nat Rev Cardiol. 2014; 11: 276-289https://doi.org/10.1038/nrcardio.2014.26
        • World Health Organization
        Cardiovascular Diseases (CVDs).
        2019 (Available from:https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).(Accessed 19 November 2019))
        • Zahid M.
        • Singla I.
        • Good C.B.
        • Stone R.A.
        • Kim S.
        • Fine M.
        • et al.
        Associations between pneumococcal vaccination and adverse outcomes in patients with suspected acute coronary syndrome.
        Adv Infect Dis. 2012; 2: 122-134