Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial

The IAMI trial was a randomized, double-blind, placebo-controlled, investigator-initiated trial designed to evaluate the efficacy of influenza vaccine after MI or percutaneous coronary intervention (PCI) in high-risk patients with coronary artery disease. The trial was conducted at 30 centers in 8 countries (Sweden, Denmark, Norway, Latvia, the United Kingdom, Czech Republic, Bangladesh, and Australia) from October 2016 through February 2020. Participants were enrolled during the Northern Hemisphere influenza season from September through February, and from May through September in the Southern Hemisphere influenza season (Bangladesh and Australia).

The trial was conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice and was approved by the Swedish Ethical Review Agency (Dnr 2014/264) and the ethical review board and national regulatory authority of each participating site. Participants provided written informed consent. Data were collected and analyzed by the investigators. The IAMI trial is registered at https://www.clinicaltrials.gov (Unique identifier: NCT02831608) and at the European Union Drug Regulating Authorities Clinical Trials Database (number 2014-001354-42).

Project coordination, medical review, data management, and site monitoring were coordinated at Örebro University Hospital. Statistical oversight and analysis were performed by statisticians at the London School of Hygiene and Tropical Medicine. The trial was overseen by a data safety and monitoring board of independent experts that periodically reviewed data by treatment group but decided not to break the code as to which group received influenza vaccine or placebo.

Because of the coronavirus disease 2019 (COVID-19) pandemic, the data safety and monitoring board recommended on April 7, 2020, that it would not be feasible for the trial to continue recruitment, because the transmission of influenza was expected to decrease, and COVID-19–related deaths were deemed likely to become common in both arms of the trial, making results difficult to interpret.

From October 1, 2016, to March 1, 2020, 6696 patients were screened, of whom 2571 provided written informed consent and underwent randomization; 2532 received influenza vaccination or placebo and were included in the modified intention-to-treat analysis (Figure 1, Table II in the Data Supplement). The baseline characteristics of the participants were well balanced between the trial groups (Table 1). The mean (±SD) age of the participants was 59.9±11.2 years, with 462 (18.2%) women, 870 (35.5%) current smokers, and 528 (21.1%) participants with diabetes. A total of 1348 (54.5%) patients were admitted with ST-segment–elevation myocardial infarction, 1119 (45.2%) with non–ST-segment–elevation myocardial infarction, and 8 (0.3%) with stable coronary artery disease. A total of 1868 participants (74.3%) were treated with PCI, and 587 (23.4%) received medical treatment only (Table III in the Data Supplement). Left ventricular ejection fraction at discharge, assessed by echocardiography, was normal in 60.5% of participants, slightly reduced in 27.5%, moderately reduced in 9.9%, and severely reduced in 2.2%. Medication at discharge reflected current clinical practice (Table III in the Data Supplement).

The primary composite end point occurred in 67 participants (5.3%) assigned to influenza vaccine and 91 participants (7.2%) assigned to placebo (HR, 0.72 [95% CI, 0.52–0.99]; P=0.040; Table 2, Figure 2). With respect to key secondary end points, the rates of all-cause death were 2.9% in the influenza vaccine group and 4.9% in the placebo group (HR, 0.59 [95% CI, 0.39–0.89]; P=0.010). Rates of cardiovascular death were 2.7% and 4.5%, respectively (HR, 0.59 [95% CI, 0.39–0.90]; P=0.014), and rates of MI were 2.0% and 2.4%, respectively (HR, 0.86 [95% CI, 0.50–1.46]; P=0.57). Causes of death were mainly cardiovascular (Table IV in the Data Supplement). None of the 8 patients in the stable coronary artery disease group experienced an event. Across all subgroups, the findings were consistent with the primary composite end point result (Figure 3). Although country was not part of the prespecified subgroups, we also tested if the treatment effect differed by country, but there was no evidence of this (interaction P=0.75).

Serious adverse events were rare and similar in type and incidence in the influenza vaccine and placebo groups (Table V in the Data Supplement). Solicited systemic reactions within the 7 days after injection were reported at a similar incidence in the 2 groups, whereas injection site reactions such as pain, redness, swelling, and hardening were reported significantly more often in participants assigned to influenza vaccine (Table VI in the Data Supplement). In both groups, ≈1 in 7 participants reported receiving influenza vaccine (Table VI in the Data Supplement). About 6% of participants reported contracting acute respiratory illness during the 12-month follow-up period (Table VI in the Data Supplement).

We searched PubMed, up to June 10, 2021, for published randomized clinical trials assessing the effect of influenza vaccination among patients with coronary artery disease. The search terms were as follows: (“coronary artery disease” or “ischemic heart disease” or “myocardial infarction”) AND (“influenza vaccination” or “influenza immunization”) AND (“clinical trial” or “randomized”). We identified 3 other trials with 1-year follow-up data that have compared influenza vaccine with no vaccine or placebo in high-risk patients with cardiovascular disease: the FLUVACS trial (FLU Vaccination Acute Coronary Syndromes and Planned Percutaneous Coronary Interventions Study; 35 cardiovascular deaths in 301 patients)⁸; the FLUCAD trial (Influenza Vaccination in Prevention From Acute Coronary Events in Coronary Artery Disease study; 4 cardiovascular deaths in 658 patients)⁹; and the study by Phrommintikul et al¹⁰ (17 cardiovascular deaths in 439 patients). The pooled estimate of cardiovascular death of the HR from the fixed-effect meta-analysis of all 4 trials was 0.51 (95% CI, 0.36–0.71); P=0.0001. There was no evidence of between-study heterogeneity (P=0.48, I²=9.7%) (Figure I in the Data Supplement). A random-effects model produced almost identical results (HR, 0.50 [95% CI, 0.35–0.73]; P=0.0003).

Among participants with MI or high-risk coronary heart disease, influenza vaccine administered within 72 hours of an invasive coronary procedure or hospitalization resulted in a lower risk at 12 months of a composite primary outcome of all-cause death, MI, or stent thrombosis, and a lower risk of all-cause death and of cardiovascular death compared with placebo, as well. The results were consistent across subgroups and in agreement with a recent meta-analysis of randomized trials and observational studies comprising almost 240 000 patients with cardiovascular disease with a median follow-up of 19.5 months reporting influenza vaccine associated with reduced risk of all-cause and cardiovascular mortality but not with MI compared with controls.¹⁴

In this study, participants assigned to influenza vaccine reported more injection site reactions than participants assigned to placebo, but there were no differences between groups in self-reported systemic reactions or in investigator-reported adverse or serious adverse events, confirming earlier findings that influenza vaccine can be safely administered after a cardiovascular event.^8,15

The greatest positive effect of influenza vaccine in patients with cardiovascular disease may be seen in the highest-risk subjects with recent acute coronary syndrome.¹⁶ This observation seems supported by our findings and the findings of the FLUVACS study (200 patients with MI and 101 for whom PCI was scheduled)⁸ where the primary end point of cardiovascular death at 1 year was significantly lower among patients assigned influenza vaccination and by the study by Phrommintikul et al¹⁰ (439 patients with acute coronary syndrome) where the primary end point of major cardiovascular events was lower among patients assigned influenza vaccination. Conversely, the FLUCAD study of 658 mostly stable patients with coronary artery disease randomly assigned to influenza vaccination or placebo revealed no difference in the composite primary end point of cardiovascular death, MI, and coronary revascularization after 1 year.⁹

The circulating strains of influenza varied over the study years, and included A(H3N2), A(H1N1)pdm09, and B. In the 2 seasons when influenza vaccine most favorably impacted outcome (2017–2018 and 2019–2020; Figure 3) the corresponding estimated vaccine effectiveness was also good, up to 60%,^17,18 whereas vaccine effectiveness was poorer in the other 2 study seasons (2016–2017 and 2018–2019).^18,20 Time-to-event curves (Figure 2) in this study began to separate early postinjection and stabilized at ≈3 months, indicative of a therapeutic effect during the vulnerable early phase post-MI characterized by a high level of inflammation.²¹ Influenza vaccination results in early immune activation with strong upregulation of genes involved in interferon signaling and antigen presentation pathways²² along with lowering of proinflammatory cytokines²³ and may exert an anti-inflammatory and plaque-stabilizing effect.²⁴ Another explanation for our findings is that influenza infection may trigger an acute cardiovascular event,³ and patients experiencing a MI are at the highest risk of a new cardiovascular event in the initial ensuing months,²⁵ a period where preventing influenza could be of particular importance.

Because influenza vaccination carries a Class I, Level of Evidence B recommendation in both American and European secondary prevention cardiovascular guidelines,^26,27 it could be considered controversial to conduct a randomized clinical trial in which half of the patients received placebo. However, current guidelines are based mostly on evidence from observational studies, timing of influenza vaccination following an acute cardiovascular event is unknown, and influenza immunization rates remain low.²⁸ In the IAMI study only patients not routinely receiving yearly influenza vaccination and not planning to be vaccinated during the current influenza season could be enrolled. Also, participants were allowed to obtain influenza vaccination after study enrollment on their own behalf. The crossover rate in the placebo arm was 13.2%. If anything, this would have biased the results toward null. The findings of the IAMI study indicate that in-hospital vaccination after MI during the influenza season is safe and offers protection equivalent to standard therapies such as statins and angiotensin-converting enzyme inhibitors.²⁹ In-hospital influenza vaccination given routinely following MI will likely also lead to higher patient treatment compliance.³⁰

This trial has several limitations. First, in part because the trial was stopped early because of the COVID-19 pandemic, the power to detect differences in the primary end point was reduced. Results of analyses of clinical trials ended early tend to exaggerate the effects of a treatment.³¹ Second, participants enrolled in Bangladesh did not routinely undergo invasive investigation and treatment, thus precluding assessment of stent thrombosis, which was one of the 3 components of the primary end point. Third, trivalent vaccine was used in the first study season and quadrivalent vaccine was used in the following seasons. Fourth, only 8 patients with high-risk stable coronary artery disease were enrolled. Last, we did not evaluate the effect of influenza vaccination outside of influenza seasons.

In participants with MI or high-risk coronary disease, in-hospital influenza vaccination resulted in a lower risk of a composite of all-cause death, MI, or stent thrombosis; lower risk of all-cause death; and lower risk of cardiovascular death at 12 months compared with placebo. In addition, our exploratory meta-analysis, for this trial plus 3 previous trials,^8–10 demonstrated a reduction by half of cardiovascular death at 1 year in patients assigned to influenza vaccination. Overall, these findings suggest that influenza vaccination should be considered as part of in-hospital treatment after MI.

The authors thank the staff at all centers participating in the IAMI study (Influenza Vaccination After Myocardial Infarction) for their professionalism and commitment in this study. They are grateful for the assistance from Uppsala Clinical Research Center, Sweden and the Western Denmark Heart Registry for baseline data extraction. They are grateful for study coordination and administration by L. Mazouch, Karolinska Trial Alliance, Karolinska University Hospital, Stockholm, Sweden and T. Blomerus, A. Eriksson, and J. Josefsson at Örebro University Hospital, Sweden. Dr Fröbert conceived the study, wrote the first draft of the study protocol, and wrote the first draft of the manuscript. All authors participated in patient recruitment and data collection. Drs Collier, Pocock, Erlinge, Christiansen, Pernow, Götberg, MacIntyre, and Fröbert analyzed the data. All authors vouch for the data and the analysis, contributed to writing the paper, and participated in the decision to publish the paper. All authors approved the final version of the manuscript to be submitted. Dr Fröbert is guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. The results will be disseminated to study participants on request and to the general public though press release, social media, and conference presentations. This trial was approved by the ethical review board and national regulatory authority of each participating site. The lead author (Dr Fröbert) affirms that this article is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.