The vaccine against seasonal influenza, available in any given year, may be one of the better in-hospital secondary-prevention measures, suggests a randomized trial in which it led to dramatically fewer deaths and lowered the risk for some nonfatal cardiac events.
In the trial with more than 2500 patients hospitalized with acute myocardial infarction (MI) or — in fewer than 1% of cases — high-risk stable coronary heart disease, half were assigned to receive the year’s standard influenza vaccine and the other half a saline placebo within 72 hours of admission or a revascularization procedure.
Vaccinated patients experienced a 28% decline in risk for the primary endpoint of death, nonfatal MI, or stent thrombosis over the following year, compared with the control group. Their all-cause mortality dropped 41%, as did their cardiovascular mortality. Their MI risk, however, was not significantly different from that of the control cohort; the rates were both less than 3%.
The results of the trial, carried out at 30 centers in eight countries over four consecutive flu seasons ending in March 2020, combined with previous smaller studies exploring the issue, “should be sufficient to establish influenza vaccination as a new standard of care as part of in-hospital treatment,” said Ole Fröbert, MD, PhD.
Although flu vaccination is in the guidelines for the hospital care of such patients in North America, Europe, and elsewhere, it isn’t in reality part of standard care most places, Fröbert, Örebro University, Sweden, noted when presenting the study, Influenza Vaccination After Myocardial Infarction (IAMI), during the virtual European Society of Cardiology (ESC) Congress 2021.
Fröbert is also principal investigator and lead author on the trial’s report published the same day in Circulation.
The IAMI results, the report states, suggest that “in-hospital vaccination after MI during the influenza season is safe and offers protection equivalent to standard therapies like statins and angiotensin-converting enzyme inhibitors. In-hospital influenza vaccination as routine following MI will likely also lead to higher patient treatment compliance.”
Even so, and despite the extensive supporting literature, IAMI can’t be considered definitive. The trial was stopped in April 2020 with just over half of its target enrollment of 4400 patients.
The data safety and monitoring board had determined “it would not be feasible for the trial to continue recruitment, since transmission of influenza was expected to decrease” during the emerging COVID-19 pandemic, Fröbert said. Also, “COVID-19–related deaths were deemed likely to become common in both arms of the trial, making results difficult to interpret.”
Because of reduced statistical power, therefore, caution should be applied when interpreting the study, observed Barbara Casadei, MD, DPhil, John Radcliffe Hospital, Oxford, England, as an invited discussant after the IAMI presentation. Halting a trial prior to full enrollment is known to exaggerate the effect size of a treatment, she noted.
Nevertheless, Casadei said, “these data clearly show that the deployment of influenza vaccination in high-risk patients with cardiovascular disease is useful.”
Also a discussant, Filippo Crea, MD, PhD, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy, speculated on a question repeatedly asked at the ESC Congress: By what mechanism can influenza be fatal in patients with recent MI? There was no difference in MI risk between the two IAMI groups, but he offered “two plausible hypotheses.”
“The vaccination may have positive and beneficial immune modulation” effects, reducing the severity of any heart failure that develops. Or, vaccination may reduce the risk of sudden death, Crea said. “It is possible to hypothesize that in some way, the vaccination reduces the arrhythmic substrate.”
Further studies “with enough power to confirm these hypotheses,” are needed, he said, but “I’m not so worried about the lack of a mechanism responsible for this benefit.” Treatments with an unknown mechanism of benefit are fairly common in medicine.
On the other hand, “if we identify the mechanism, then we can perhaps identify new targets,” Crea said.
“For those who are interested in the mechanism, I think we still don’t know why it works — whether it is a specific effect on cardiovascular events, or whether it’s protection of the high-risk patient,” for example, Casadei said.
“But it doesn’t really matter that much. The two take-home messages here for public health are, vaccinations should be applied by risk,” she said. “Age is part of the risk but not the only part.”
And, “we need to vaccinate where we can. If these patients present to the hospital, they should be vaccinated there and then.”
Of the 1290 patients assigned to vaccination and 1281 control patients in the trial — conducted in four European countries, Australia, and Bangladesh — 54.5% had been hospitalized with ST-segment-elevation MI (STEMI), 45.2% with non-STEMI, and a few others with stable coronary disease. Three fourths of the population underwent percutaneous coronary intervention. Overall, their mean age was 60 years, and only 18.2% were women.
Rates of the composite primary outcome were 5.3% for those who were vaccinated and 7.2% for those who received placebo, for a hazard ratio (HR) of 0.72 (95% CI, 0.52 – 0.99; P = .040), Fröbert reported.
All-cause mortality was 2.9% for vaccinated and 4.9% for controls (HR, 0.59; 95% CI, 0.39 – 0.89; P = .010). The deaths were overwhelmingly cardiovascular in nature; the rates were 2.7% and 2.4%, respectively (P = .014). But MI rates during follow-up were not statistically different at 2.0% and 2.4%, respectively (P = .57).
Vaccination was associated with more of the expected adverse effects, such as injection-site pain or swelling, but the small rates of serious adverse events were similar in both groups.
It’s unknown whether influenza vaccination would be as protective in between flu seasons, Fröbert told theheart.org | Medscape Cardiology. “But we know from registry studies and from previous smaller trials that there could be an effect extended throughout the year, a so-called pleiotropic effect, but we cannot say for sure.”
After his formal IAMI presentation, Fröbert commented on the ethics of randomly assigning patients to a placebo when influenza vaccination boasts a class I, level of evidence B recommendation in the guidelines. Those guidelines, he reminded viewers, derive from observational studies and, anyway, are frequently not followed.
Also, the trial entered only patients without plans to be vaccinated for influenza, and they were not prohibited from obtaining vaccinations any time after enrollment. “We also excluded patients if the investigator deemed there was a particularly strong indication for vaccination.”
IAMI was supported by an unrestricted grant from Sanofi Pasteur, which provided the vaccine.
European Society of Cardiology Congress 2021: Hot Line–IAMI. Presented August 30, 2021.
Circulation. Published online August 30,2021. Full text
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