Jacob A. Udell, MD, MPH, FRCPC

It is impressive that the team from Mount Sinai were able to cull together almost 30 million patients from the National Inpatient Sample from 2014 to look at whether patients who were vaccinated in-hospital had a future cardiac event, particularly MI or unstable angina, in that year of follow-up. It was impressive that they were able to analyze such a large sample size. That certainly helps to make it a more powerful analysis.

It was not surprising, but it was reassuring, that there was no harm with getting a vaccine and that, after adjusting for differences in the population, there is a modest 8% lower risk for STEMI, non-STEMI and unstable angina. This is great news and another finding that should reinforce that the flu shot is helpful. Not only does it protect you from eventually getting the flu, but that there may be some further downstream complications that are avoided, like MI.

When I was training and practicing in Boston, as part of our routine checks of our performance of clinical care and receiving good teaching on the wards by my cardiology mentors, during flu vaccine season, we were asked to ask patients if they have gotten a flu shot, and to provide the flu shot if the patient did not have one. We were audited on that and we got report cards. That was a good thing because this is the kind of study that reinforces that clinical practice. Clearly it is not happening a lot. We do not know from this study how many people in the study got a flu vaccine outside of being hospitalized, so it is certainly not being utilized often. It was less than 1% utilization. We know that it is not the primary source of people getting their flu shot nor did we suspect that, but there may be an opportunity for growth. This study does suggest that there is no harm and maybe benefit. For clinical practice, the hospital should have a policy of screening their patients and providing that feedback to the physicians. It shouldn’t be surprising to patients, who can’t walk through a hospital or pharmacy without seeing signs saying, “Did you get your flu shot? It’s flu vaccine season, talk to your doctor or pharmacist.”

There are many limitations to an analysis like this. A cohort study where people got a vaccine vs. no vaccine can be confounded by the recipients having some reason for getting a vaccine that itself is also associated with healthier outcomes. We cannot tell from a study like this whether it is causal or simply a marker of better CV health There are some data to suggest the confounding is quite ripe in this field.

There are three clinical trials currently going on to answer this question definitively. A number of small trials have already looked at the benefit of flu vaccine to reduce CV risk individually. I was fortunate to lead a meta-analysis of those trials that we published a few years ago (Udell JA, et al. JAMA. 2013;doi:10.1001/jama.2013.279206.). That was very suggestive that influenza vaccine might reduce the risk of adverse CV events. The highest risk patients derived most of the CV benefit too.

We were subsequently fortunate to get funded by the NIH to do an approximately 9,000-patient trial called INVESTED. The design paper was published last year in the American Heart Journal (doi: 10.1016/j.ahj.2018.05.007) and on clinicaltrials.gov (NCT02787044). INVESTED is looking at a strategy of patients in the U.S. and Canada receiving in a double-blinded fashion a standard dose vaccine that covers four strains of flu vs. a high-dose vaccine with the usual three strains of flu protein. In theory, the high-dose vaccine should boost the immune system’s response to provide more robust flu protection compared with standard dose vaccines, which may translate into improved CV outcomes, the main focus of our trial.

The comparative effectiveness trial will demonstrate for the first time whether a more effective vaccine strategy can impact hard CV outcomes — all-cause death or being hospitalized for a heart or lung condition.

There are two other trials that have been funded and are ongoing. One is being led out of Sweden called IAMI (NCT02831608). That is a placebo-controlled trial of vaccine vs. placebo in patients with recent MI or high-risk coronary PCI evaluating whether vaccination reduces coronary outcomes.

The other trial is being led from McMaster called IVVE (NCT02762851) that also had a design paper in the American Heart Journal (Loeb M, et al. Am Heart J. 2019;doi:10.1016/j.ahj.2019.02.009.). This study is a placebo-controlled study of flu vaccine in patients with HF in middle-income and low-income countries; the investigators are looking to see if the vaccine impacts broad cardiac outcomes.

These trials have the ability to disentangle what until now has been a promising association from true causation.

The authors should be congratulated on their work. I would love to probe a little bit further to determine if any differences were seen according to the timing of the flu vaccine (fall vs. spring).

At present, there are no further details about whether the researchers were able to adjust for differences in clinical characteristics. Age, gender, ethnicity and socioeconomic status are mentioned, but not CVD or other clinical conditions. Since the study had 29 million people, investigators can probably compare patients with heart disease vs. those who do not to see whether the association was robust in those that have heart disease, diabetes or other major risk factors. Those are areas where further research could be done in this field with their dataset.