A Sixfold Increase, More If No CVD History

The link between influenza infection and a rise in short-term risk for acute myocardial infarction (MI) has been reaffirmed in a new study, which showed the risk appears to be particularly elevated in individuals with no prior diagnosis of coronary artery disease.

“Our study results confirm previous findings of an increased risk of MI during or immediately following acute severe flu infection and raises the idea of giving prophylactic anticoagulation to these patients,” reported Patricia Bruijning-Verhagen, MD, University Medical Center Utrecht, Utrecht, the Netherlands, who is the senior author of the study, which was published online in NEJM Evidence.

“Our results also change things — in that we now know the focus should be on people without a history of cardiovascular disease — and highlight the importance of flu vaccination, particularly for this group,” she pointed out.

The observational, self-controlled, case-series study linked laboratory records on respiratory virus PCR testing from 16 laboratories in the Netherlands to national mortality, hospitalization, medication, and administrative registries. Investigators compared the incidence of acute MI during the risk period — days 1-7 after influenza infection — with that in the control period — 1 year before and 51 weeks after the risk period.

The researchers found 26,221 positive PCR tests for influenza, constituting 23,405 unique influenza illness episodes. Of the episodes of acute MI occurring in the year before or the year after confirmed influenza infection and included in the analysis, 25 cases of acute MI occurred on days 1-7 after influenza infection and 394 occurred during the control period.

The adjusted relative incidence of acute MI during the risk period compared with during the control period was 6.16 (95% CI, 4.11-9.24).

The relative incidence of acute MI in individuals with no previous hospitalization for coronary artery disease was 16.60 (95% CI, 10.45-26.37); for those with a previous hospital admission for coronary artery disease, the relative incidence was 1.43 (95% CI, 0.53-3.84).

A temporary increase in the risk for MI has been reported in several previous studies. A 2018 Canadian study by Kwong et al showed a sixfold elevation in the risk for acute MI after influenza infection, which was subsequently confirmed in studies from the United States, Denmark, and Scotland.

In their study, Bruijning-Verhagen and her colleagues aimed to further quantify the association between laboratory-confirmed influenza infection and acute MI and to look at specific subgroups that might have the potential to guide a more individualized approach to prevention.

They replicated the Canadian study using a self-controlled case-series design that corrects for time-invariant confounding and found very similar results: A sixfold increase in the risk for acute MI in the first week after laboratory-confirmed influenza infection.

“The fact that we found similar results to Kwong et al strengthens the finding that acute flu infection is linked to increased MI risk. This is becoming more and more clear now. It also shows that this effect is generalizable to other countries,” Bruijning-Verhagen said.

People Without Cardiovascular Disease at Highest Risk 

The researchers moved the field ahead by also looking at whether there is a difference in risk between individuals with flu who already had cardiovascular disease and those who did not.

“Most previous studies of flu and MI didn’t stratify between individuals with and without existing cardiovascular disease. And the ones that did look at this weren’t able to show a difference with any confidence,” Bruijning-Verhagen explained. “There have been suggestions before of a higher risk of MI in individuals with acute flu infection who do not have existing known cardiovascular disease, but this was uncertain.” 

The current study showed a large difference between the two groups, with a much higher risk for MI linked to flu in individuals without any known cardiovascular disease.

“You would think patients with existing cardiovascular disease would be more at risk of MI with flu infection, so this was a surprising result,” reported Bruijning-Verhagen. “But I think the result is real. The difference between the two groups was too big for it not to be.”

Influenza can cause a hypercoagulable state, systemic inflammation, and vascular changes that can trigger MI, even in patients not thought to be at risk before, she pointed out. And this is on top of high cardiac demands because of the acute infection.

Patients who already have cardiovascular disease may be protected to some extent by the cardiovascular medications that they are taking, she added.

These results could justify the use of short-term anticoagulation in patients with severe flu infection to cover the high-risk period, Bruijning-Verhagen suggested. “We give short-term anticoagulation as prophylaxis to patients when they have surgery. This would not be that different. But obviously, this approach would have to be tested,” she said.

Clinical studies looking at such a strategy are currently underway.

‘Get Your Flu Shot’

The results reinforce the need for anyone who is eligible to get the flu vaccine. “These results should give extra weight to the message to get your flu shot,” she said. “Even if you do not consider yourself someone at risk of cardiovascular disease, our study shows that you can still have an increased risk of MI as a result of severe flu infection.” 

In many countries, the flu vaccine is recommended for everyone older than 60 or 65 years and for younger people with a history of cardiovascular disease. Data on flu vaccination was not available in the current study, but the average age of patients infected with flu was 74 years, so most patients would have been eligible to receive vaccination, she said.

In the Netherlands where the research took place, flu vaccination is recommended for everyone older than 60 years, and uptake is about 60%.

“There will be some cases in younger people, but the number needed to vaccinate to show a benefit would be much larger in younger people, and that may not be cost-effective,” reported Bruijning-Verhagen.

Flu vaccination policies vary across the world, with many factors being taken into account; some countries already advocate for universal vaccination every year.

Extend Flu Vaccination to Prevent ACS 

This study “provides further impetus to policy makers to review and update guidelines on prevention of acute coronary syndromes,” Raina MacIntyre, MBBS, Zubair Akhtar, MPH, and Aye Moa, MPH, University of New South Wales Sydney, Sydney, Australia, wrote in an accompanying editorial.

“Although vaccination to prevent influenza is recommended and funded in many countries for people 65 years of age and older, the additional benefits of prevention of ACS [acute coronary syndromes] have not been adopted universally into policy and practice nor have recommendations considered prevention of ACS in people 50-64 years of age,” they added.

“Vaccination is low-hanging fruit for people at risk of acute myocardial infarction who have not yet had a first event. It is time that we viewed influenza vaccine as a routine preventive measure for ACS and for people with coronary artery disease risk factors, along with statins, blood pressure control, and smoking cessation,” she explained.

The question of whether the link found between elevated MI risk and severe flu infection might be the result of MI being more likely to be detected in patients hospitalized with severe flu infection, who would undergo a thorough workup, was raised in a second editorial by Lori Dodd, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

“I think this would be very unlikely to account for the large effect we found,” responded Bruijning-Verhagen. “There may be the occasional silent MI that gets missed in patients who are not hospitalized, but, in general, acute MI is not something that goes undetected.”