Repeated Annual Seasonal Influenza Vaccination of Patients With Circulatory Disease as Secondary Prevention of Cardiovascular Events: an Additional Self-Controlled Case Series Analysis

Aim     To assess the effect of annual seasonal flu vaccination for 3 years on the risk of acute respiratory infection (ARI) and cardiovascular events (CVE) in cardiological patients followed up using two analytical methods.

Material and methods            This prospective comparative study included 817 patients in October 2012. CVE, other chronic non-communicable diseases, and ARI recorded from October 2012 through November 2015 were analyzed. Vaccinated and unvaccinated patients were compared using survival curves and a self-controlled case series method for paired 6-month periods. Differences were considered statistically significant at p<0.05.

Results            The analysis included 813 patients (mean age, 63.3±11.6 years; 40.5% men; in the 2012/13-2013/14-2014/15 season, 45-44-41% of patients, respectively, were vaccinated; 1, 2, and 3 vaccinations were received by 60, 57, and 285 patients, respectively; 413 were unvaccinated). Compared to unvaccinated patients, the patients vaccinated three times developed the first ARI later (p<0.0001); the relative risk of developing cardiovascular complications (CVC) was 0.88 (95% confidence interval: 0.65-1.10). Among vaccinated patients, there were fewer patients with ARI (p<0.001) and cardiovascular diseases (p=0.02) not only in summer compared to winter, but also in summer, ARI developed in 41.2% fewer patients than in unvaccinated (p=0.002).

Conclusion      The use of two analytical methods allowed us to identify additionally both non-specific and persistent specific effects of three-year flu immunization in cardiological patients in summer, which needs to be confirmed in randomized placebo-controlled studies.

1. Behrouzi B, Udell JA. Universal flu vaccines: a shot at lifelong cardioprotection? Nature Reviews Cardiology. 2022;19(3):145–6. DOI: 10.1038/s41569-021-00670-w

2. Fröbert O, Cajander S, Udell JA. The ideal vaccine to prevent cardiovascular disease. European Heart Journal. 2023;44(7):621–3. DOI: 10.1093/eurheartj/ehac826

3. Davidson JA, Banerjee A, Douglas I, Leyrat C, Pebody R, McDonald HI et al. Primary prevention of acute cardiovascular events by influenza vaccination: an observational study. European Heart Journal. 2023;44(7):610–20. DOI: 10.1093/eurheartj/ehac737

4. Ciszewski A, Bilinska ZT, Brydak LB, Kepka C, Kruk M, Romanow ska M et al. Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study. European Heart Journal. 2008;29(11):1350–8. DOI: 10.1093/eurheartj/ehm581

5. Gurfinkel EP, Leon de la Fuente R, Mendiz O, Mautner B. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) Study One-year follow-up. European Heart Journal. 2004;25(1):25–31. DOI: 10.1016/j.ehj.2003.10.018

6. Phrommintikul A, Kuanprasert S, Wongcharoen W, Kanjanavanit R, Chaiwarith R, Sukonthasarn A. Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome. European Heart Journal. 2011;32(14):1730–5. DOI: 10.1093/eurheartj/ehr004

7. Fröbert O, Götberg M, Erlinge D, Akhtar Z, Christiansen EH, Mac Intyre CR et al. Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Circulation. 2021;144(18):1476–84. DOI: 10.1161/CIRCULATIONAHA.121.057042

8. Davis MM, Taubert K, Benin AL, Brown DW, Mensah GA, Baddour LM et al. Influenza Vaccination as Secondary Prevention for Cardiovascular Disease. Journal of the American College of Cardiology. 2006;48(7):1498–502. DOI: 10.1016/j. jacc.2006.09.004

9. Smith DJ, Forrest S, Ackley DH, Perelson AS. Variable efficacy of repeated annual influenza vaccination. Proceedings of the National Academy of Sciences. 1999;96(24):14001–6. DOI: 10.1073/ pnas.96.24.14001

10. Mironov A.N., Merkulov V.A., Bunyatyan V.A., Bondarev V.P., Borisevich I.V., Gorbunov M.A. et al. Guidelines for conducting clinical trials of medicines (immunobiological medicines). Part 2. - M.: Grif and K; 2013. - 212p. https://namdu.uz/media/Books/pdf/2024/10/26/NamDU-ARM-13801-Руководство_по_проведению_клинических_исследований_prwHaSq.pdf

11. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination. New England Journal of Medicine. 2004;351(25):2611–8. DOI: 10.1056/NEJMoa041747

12. Warren-Gash C, Hayward AC, Hemingway H, Denaxas S, Thomas SL, Timmis AD et al. Influenza Infection and Risk of Acute Myocardial Infarction in England and Wales: A CALIBER Self-Controlled Case Series Study. The Journal of Infectious Diseases. 2012;206(11):1652–9. DOI: 10.1093/infdis/jis597

13. Blackburn R, Zhao H, Pebody R, Hayward A, Warren-Gash C. Laboratory-Confirmed Respiratory Infections as Predictors of Hospital Admission for Myocardial Infarction and Stroke: Time-Series Analysis of English Data for 2004–2015. Clinical Infectious Diseases. 2018;67(1):8–17. DOI: 10.1093/cid/cix1144

14. Boytsov S.A., Loukianov M.M., Platonova E.V., Gorbunov V.M., Romanchuk S.V., Nazarova O.A. et al. Efficiency of Influenza Vaccination in Patients with Circulatory System Diseases under Dispensary Observation in Outpatient Clinics: Prospective Follow up Monitoring Data. Rational Pharmacotherapy in Cardiology. 2016;12(6):703–10. DOI: 10.20996/1819-6446-2016-12-6-703-710

15. Lewnard JA, Cobey S. Immune History and Influenza Vaccine Effectiveness. Vaccines. 2018;6(2):28. DOI: 10.3390/vaccines6020028

16. Whitaker HJ, Hocine MN, Farrington CP. The methodology of self-controlled case series studies. Statistical Methods in Medical Research. 2009;18(1):7–26. DOI: 10.1177/0962280208092342

17. Whitaker HJ, Paddy Farrington C, Spiessens B, Musonda P. Tutorial in biostatistics: the self‐controlled case series method. Statistics in Medicine. 2006;25(10):1768–97. DOI: 10.1002/sim.2302

18. Farrington CP. Relative incidence estimation from case series for vaccine safety evaluation. Biometrics. 1995;51(1):228–35. PMID: 7766778

19. Behrouzi B, Bhatt DL, Cannon CP, Vardeny O, Lee DS, Solomon SD et al. Association of Influenza Vaccination With Cardiovascular Risk: A Meta-analysis. JAMA Network Open. 2022;5(4):e228873. DOI: 10.1001/jamanetworkopen.2022.8873

20. Aïdoud A, Gana W, Poitau F, Fougère B, Angoulvant D. Does the influenza A vaccine have a direct atheroprotective effect? Archives of Cardiovascular Diseases. 2022;115(6–7):331–4. DOI: 10.1016/j.acvd.2022.01.005

21. Platonova E.V., Deev A.D., Lukianov М.М., Nazarova O.A., Kravtsova E.A., Furman N.V. et al. Cardiovascular disease risk after acute respiratory infection or annual influenza vaccination for 5 years. Preventive Medicine. 2018;21(2–2):19.

22. Platonova E.V., Deev A.D., Gorbunov V.M., Nazarova O.A., Belova O.A., Furman N.V. et al. Annual influenza vaccination of patients with cardiovascular diseases and changes in hemagglutinin antibody titers: 3-year follow-up data. Epidemiology and Infectious Diseases. 2020;25(2):88–101. DOI: 10.17816/EID41764

23. Boytsov S.A., Lukianov М.М., Platonova E.V., Gorbunov V.M., Romanchuk S.V., Nazarova O.A. et al. Investigation of the efficiency and safety of influenza vaccination in patients with circulatory system diseases. Preventive Medicine. 2014;17(6):13–20. DOI: 10.17116/profmed201417613-20

24. Tay C, Kanellakis P, Hosseini H, Cao A, Toh B-H, Bobik A et al. B Cell and CD4 T Cell Interactions Promote Development of Atherosclerosis. Frontiers in Immunology. 2020;10:3046. DOI: 10.3389/fimmu.2019.03046

25. Bermúdez-Fajardo A, Oviedo-Orta E. Influenza vaccination promotes stable atherosclerotic plaques in apoE knockout mice. Atherosclerosis. 2011;217(1):97–105. DOI: 10.1016/j.atherosclerosis.2011.03.019

26. Veljkovic V, Glisic S, Veljkovic N, Bojic T, Dietrich U, Perovic VR et al. Influenza vaccine as prevention for cardiovascular diseases: Possible molecular mechanism. Vaccine. 2014;32(48):6569–75. DOI: 10.1016/j.vaccine.2014.07.007

27. Chorell E, Olsson T, Jansson J-H, Wennberg P. Lysophospholipids as Predictive Markers of ST-Elevation Myocardial Infarction (STEMI) and Non-ST-Elevation Myocardial Infarction (NSTEMI). Metabolites. 2020;11(1):25. DOI: 10.3390/metabo11010025

28. Yavelov I.S., Gratsiansky N.A. Register of Acute Coronary Syndromes in Russia: Treatment and Inhospital Outcomes in Non-ST Elevation Acute Coronary Syndrome. Kardiologiia. 2003;43(12):23–36.

29. Collet J-P, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent STsegment elevation. European Heart Journal. 2021;42(14):1289– 367. DOI: 10.1093/eurheartj/ehaa575

30. Barbarash O.L., Komarov A.L., Panchenko E.P., Staroverov I.I., Shahnovich R.M., Yavelov I.S. Eurasian clinical guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Eurasian heart journal. 2021;4(37):6–59. DOI: 10.38109/2225-1685-2021-4-6-59

31. Fröbert O, Götberg M, Erlinge D, Akhtar Z, Christiansen EH, Mac Intyre CR et al. Clinical impact of influenza vaccination after ST- and non-ST-segment elevation myocardial infarction - insights from the IAMI trial. American Heart Journal. 2023;255:82–9. DOI: 10.1016/j.ahj.2022.10.005

32. 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(18):1485–8. DOI: 10.1161/CIRCULATIONAHA.121.057534

33. Byrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A et al. 2023 ESC Guidelines for the management of acute coronary syndromes. European Heart Journal. 2023;44(38):3720–826. DOI: 10.1093/eurheartj/ehad191