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Influenza virus vaccine reduces risk of ischemic events: time for a large-scale randomized trial?

2013; Future Medicine; Volume: 10; Issue: 1 Linguagem: Inglês

10.2217/fca.13.95

1744-8298

C. Raina MacIntyre, Anita Heywood, Pramesh Kovoor,

interferon and immune responses

Future CardiologyVol. 10, No. 1 CommentaryFree AccessInfluenza virus vaccine reduces risk of ischemic events: time for a large-scale randomized trial?Raina C MacIntyre, Anita E Heywood & Pramesh KovoorRaina C MacIntyre*Author for correspondenceSchool of Public Health & Community Medicine, UNSW Medicine, University of New South Wales, Australi. , Anita E HeywoodSchool of Public Health & Community Medicine, UNSW Medicine, University of New South Wales, Australi & Pramesh KovoorDepartment of Cardiology, Westmead Hospital, Sydney, AustraliaThe Westmead Clinical School, Westmead Millennium Institute for Medical Research, University of Sydney, AustraliaPublished Online:18 Dec 2013https://doi.org/10.2217/fca.13.95AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: coronary artery diseaseinfluenza vaccinepreventionIn 2008, ischemic heart disease overtook infectious diseases as the leading cause of death in the world [101], making this the leading public health challenge globally. Accepted public health interventions to reduce or prevent the risk of coronary artery disease (CAD) include antihypertensive therapy, smoking cessation interventions and lipid-lowering drugs. These target known major risk factors for CAD, and are therefore the mainstay of coronary prevention. The influenza vaccine has long been identified as reducing the risk of cardiovascular events [1], but is not accepted as an intervention for CAD prevention.Influenza causes a substantial burden of disease and deaths, especially at the extremes of age every year during the winter seasson. Influenza-related morbidity and mortality includes severe respiratory infection and pneumonia, which may be primary viral or secondary bacterial in cause [2]. However, worsening of underlying chronic diseases and precipitation of cardiovascular events are also recognized complications of influenza [3]. Many studies have shown that influenza contributes to all-cause mortality and to cardiovascular and respiratory hospitalizations [4,5]. In addition, rates of acute myocardial infarction (AMI) and death peak every year during the influenza season [6]. Other acute infections have also been associated with AMI [7]. Influenza and other infections, through fever, tachycardia and cytokine release, can result in plaque disruption, hypoxemia and a prothrombotic state. Influenza is trophic to vascular tissue, perhaps explaining the specific association of influenza with AMI [8]. These factors, in turn, can precipitate acute thrombosis within an already-diseased coronary artery, even one with a less than critical level of stenosis [7].In recognition of the major burden of disease caused by influenza in the elderly, many countries recommend and fund annual influenza vaccinations for people aged 65 years and over [9,102]. Trivalent, inactivated influenza vaccines (TIVs) confer immunity that is specific to the two influenza A and one influenza B strains in the vaccine. Vaccination is required annually as vaccine-induced immunity wanes and is strain-specific, and different strains predominate from year to year. The efficacy of TIVs in adults aged 18–65 years is approximately 67% against influenza [10]. The effectiveness of TIV against AMI has been shown to be 45% [11]. A range of case–control and cohort studies have demonstrated that TIV protects against AMI [1], but such studies are subject to the limitations of observational epidemiology.To date, only three small-scale randomized controlled clinical trials (RCTs) of influenza vaccine in AMI prevention have been conducted, all suggesting protective efficacy against composite outcomes for major adverse coronary events in patients who have already had an acute coronary event. The FLUVACS study included subjects with known CAD who were randomized to TIV or placebo and followed up at 6 months, 1 year and 2 years. Vaccinated subjects had lower mortality and major adverse cardiovascular events compared with controls [12–14]. In the FLUCAD trial of 658 subjects with CAD, one composite end point, but not others, was significantly lower in the vaccinated group [15]. This composite end point included major adverse coronary events (cardiovascular death, myocardial infarction or coronary revascularization) or hospitalization for myocardial ischemia. In the PROBE trial of 439 subjects with acute coronary syndrome, influenza vaccination resulted in a significant reduction of major coronary adverse events, but not cardiovascular death [16]. These RCTs are consistent with the body of observational epidemiologic studies, which show that influenza is associated with CAD. A pooled analysis of FLUVAC and FLUCAD showed a significant reduction of cardiovascular death in vaccinated subjects, but the small numbers make it difficult to draw conclusions about other outcomes such as AMI [17].A substantial burden of CAD occurs in the 50–64 years age group, who are not routinely funded for the influenza vaccine, as adults are >65 years. The published RCTs studied the influenza vaccine in subjects with existing or acute CAD, which is already a vaccine recommendation in many developed countries. Rates of vaccination for targeted programs are generally much lower than for broader, age-based recommendations. A broader policy question regards the potential of the vaccine to prevent first CAD events in people at risk. The first presentation of CAD may be sudden death, therefore prevention of first CAD events is also a worthy target. For countries that already have a recommendation for influenza vaccine for adults aged >65 years, extending the age group to 50 years and above may have a greater population health impact than a targeted recommendation for people with CAD. The influenza vaccine has already been shown to be cost effective for adults aged 50–64 years on the basis of influenza prevention alone, thus factoring in the potential impact on CAD would make this even more favorable as a population health intervention. Furthermore, influenza vaccine efficacy is higher in adults 65 years, improving potential cost–effectiveness even more. On a population health level, we accept antihypertensives, smoking cessation and lipid-lowering drugs as major interventions to prevent CAD. Antihypertensive medications and statins each have an effectiveness in reducing coronary vascular events of approximately 20–25% [18,19]. If influenza vaccine reduces the risk of AMI by 45% [11], this is greater than the efficacy of statins and antihypertensives, making the potential population health impact of vaccination significant.The existing evidence regarding influenza vaccine is compelling, but has not influenced policy or practice. Vaccination policy surrounding influenza does not routinely consider CAD impacts, neither is the influenza vaccine compared in cost–effectiveness to accepted CAD interventions such as statins or antihypertensives. The influenza vaccine is cheap, safe and may be 'low hanging fruit' for CAD prevention, but needs to be incorporated into policy and practice to have an impact. What is needed to influence policy is a large RCT, sufficiently powered to look at CAD prevention in all adults aged over 50 years, regardless of whether they have had a CAD event. The outcomes in such a trial should include first CAD events in previously healthy adults, as well as second events in people with existing CAD. Such a trial would need to be much larger in scale than the trials published to date. Increasingly, vaccines against infectious diseases are becoming relevant for chronic disease prevention, with other examples being hepatitis B and human papillomavirus vaccines. Given that CAD is now the leading cause of death in the world, a RCT of influenza vaccine for CAD prevention that is adequately powered to provide definitive evidence, would be timely and worthwhile.Financial & competing interests disclosureCR MacIntyre has received grant funds and/or support for investigator-driven research from GSK, CSL, Sanofi Pasteur, Merck and Pfizer. AE Heywood has received grant funds for investigator-driven research from GSK and Sanofi Pasteur. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 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.9(10),601–610 (2009).Crossref, Medline, Google Scholar2 Rothberg MB, Haessler SD, Brown RB. Complications of viral influenza. Am. J. Med.121,258–264 (2008).Crossref, Medline, Google Scholar3 Fiore AE, Uyeki TM, Broder K et al. Prevention and control of influenza with vaccines: recommendations of the advisory committee on immunization practices (ACIP), 2010. MMWR Recomm. Rep.59(RR-8),1–62 (2010).Medline, Google Scholar4 Upshur RE, Goel V. 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Department of Health, London, UK (2013). www.gov.uk/government/publications/green-book-the-complete-current-editionGoogle ScholarFiguresReferencesRelatedDetailsCited ByModelling the influenza disease burden in people aged 50–64 and ≥65 years in Australia29 September 2021 | Influenza and Other Respiratory Viruses, Vol. 16, No. 1If there were a vaccine against acute myocardial infarction, would you use it?C Raina MacIntyre & Aye M Moa23 August 2017 | Future Cardiology, Vol. 13, No. 5Influenza vaccine as a coronary intervention for prevention of myocardial infarction29 September 2016 | Heart, Vol. 102, No. 24 Vol. 10, No. 1 Follow us on social media for the latest updates Metrics History Published online 18 December 2013 Published in print January 2014 Information© Raina MacIntyreKeywordscoronary artery diseaseinfluenza vaccinepreventionFinancial & competing interests disclosureCR MacIntyre has received grant funds and/or support for investigator-driven research from GSK, CSL, Sanofi Pasteur, Merck and Pfizer. AE Heywood has received grant funds for investigator-driven research from GSK and Sanofi Pasteur. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download