By Michael H. Crawford, MD, Editor

SYNOPSIS: A randomized, controlled trial of influenza vaccine vs. placebo in patients with acute myocardial infarction or at high risk for coronary artery disease inoculated during the index hospitalization showed a lower risk of the combined endpoint of death, myocardial infarction, or stent thrombosis at one year.

SOURCE: Fröbert O, Götberg M, Erlinge D, et al. Influenza vaccination after myocardial infarction: A randomized, double-blind, placebo-controlled, multicenter trial. Circulation 2021;144:1476-1484.

Observational studies have shown an association between the risk of cardiovascular (CV) events and influenza, but clinical trials of influenza vaccine for preventing CV events have been inconclusive.1,2 Fröbert et al designed the Influenza Vaccination After Myocardial Infarction (IAMI) trial to test the hypothesis that influenza vaccination in patients with high-risk coronary artery disease (CAD) or recent myocardial infarction (MI) would reduce the subsequent incidence of death, MI, or stent thrombosis.

IAMI was a randomized, double-blind, placebo-controlled study conducted in 30 centers in six European countries, Bangladesh, and Australia during their influenza seasons. From 2016 to early 2020, 2,532 patients (mean age 60 years, 18% women), were enrolled in the intention-to-treat analysis. Acute ST-elevation MI (STEMI) was present in 55% and non-STEMI in 45%. Less than 1% exhibited stable high-risk CAD. Influenza vaccine or placebo was administered within 72 hours of an invasive procedure or hospital admission. The primary composite endpoint occurred in 5.3% of the vaccine arm and 7.2% of the placebo arm (HR, 0.72; 95% CI, 0.52-0.99; P = 0.04). All-cause mortality was 2.9% in the influenza vaccine group and 4.9% in the placebo group (HR, 0.59; 95% CI, 0.39-0.89; P = 0.01). The causes of death were largely CV disease-related, and the risk of CV death alone was 2.9% vs. 4.5% (HR, 0.59; 95% CI, 0.39-0.90; P = 0.014). All subgroups analyzed showed the same results. When combined with the results of three smaller randomized, controlled trials in a meta-analysis, the results were similar in general, but more impressive for CV deaths (HR 0.51; 95% CI, 0.36-0.71; P = 0.0001). The authors concluded influenza vaccine early after MI significantly lowered the composite risk of all-cause death, MI, or stent thrombosis; the risk of all-cause mortality; and CV death.

COMMENTARY

The association of viral infections with a higher risk of CV events has been well established. The inflammation accompanying such infections can trigger plaque rupture and depress global myocardial function. In addition, so-called type 2 or supply/demand imbalance infarction can be precipitated by the fever, tachycardia, and hypoxia that accompanies influenza. It has been estimated that 10% to 15% of influenza patients develop CV events, which can lead to ICU admission and even death.3 Guidelines recommend influenza vaccination for all patients with CAD.4 However, vaccination in patients hospitalized for acute MI has not been studied extensively, and there is concern the inflammatory response to the vaccine may be deleterious. These realities make this report from the IAMI trial of interest.

Despite ending the trial early because of the onset of the COVID-19 pandemic, these results are remarkable considering vaccination was on top of excellent standard care for these patients. Also, the benefits were seen early as the time to a CV events curves separated at three months of follow up. In addition, the results were consistent in the predefined subgroups analyzed and in a meta-analysis of three smaller randomized trials. Adverse effects of the vaccine mainly were injection site reactions, which were more frequent than in the placebo group. Systemic or serious reactions were few and no different than those seen in the placebo group.

There were weaknesses in this study. Patients in Bangladesh were less likely to receive stents, which reduced the power of detecting differences in stent thrombosis. Also, there were only eight patients with high-risk stable CAD, so the conclusions may not apply to this group. Inexplicably, only 19% of subjects were women, but there did not appear to be a different result in this subgroup. Finally, the study was conducted only during flu season, alternating between hemispheres.

When added to other related data, the results of IAMI should be enough to sway the guidelines toward including influenza vaccine in the post-MI recommendations. Experience with the influenza vaccine in all stable CAD patients as currently recommended suggests only about half of such patients are vaccinated for influenza. The key message of the IAMI trial is vaccination should happen in the hospital when patients are admitted for CV events. Not only would such a policy likely increase vaccination rates in CAD patients, but also would reduce subsequent CV morbidity and mortality.

REFERENCES

  1. Kwok CS, Aslam S, Kontopantelis E, et al. Influenza, influenza-like symptoms and their association with cardiovascular risks: A systematic review and meta-analysis of observational studies. Int J Clin Pract 2015;69:928-937.
  2. Yedlapati SH, Khan SU, Talluri S, et al. 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.
  3. Chow EJ, Rolfes MA, O’Halloran A, et al. Acute cardiovascular events associated with influenza in hospitalized adults: A cross-sectional study. Ann Intern Med 2020;173:605-613.
  4. Centers for Disease Control & Prevention. Flu & people with heart disease or history of stroke. Page last reviewed Aug. 26, 2021.