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Standard Dose Influenza Vaccine as Effective as High Dose Influenza Vaccine for those with Cardiovascular Disease


JAMA. 2021 Jan 5;325(1):39-49. doi: 10.1001/jama.2020.23649

Study Summary

This study was conducted to determine if patients over 65 years who were considered “high cardiac risk” (with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor) benefit more from the high dose trivalent influenza vaccine compared to the standard dose quadrivalent vaccine. It included 5260 participants for up to 3 influenza seasons in the US and Canada.

In the high-dose trivalent vaccine group, there were 975 primary outcomes (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years).

In the standard-dose quadrivalent vaccine group, there were 924 primary outcomes (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years).

This resulted in a hazard ratio = 1.06 [95% CI, 0.97-1.17]; P = .21, a non-significant difference.

Concerning adverse events, 40.5% of those in the high-dose group had a vaccine related adverse event with 2.1% of those considered severe vs 34.4% in the standard group with 1.7% severe. (a NNH of about 15)


The standard dose influenza quadrivalent vaccine in those at high risk for adverse cardiovascular complications of an influenza infection was as efficacious as the high dose trivalent vaccine and caused fewer adverse events.


This is a complicated paper. It used the High Dose Trivalent vaccine vs the Standard Dose Quadrivalent vaccine. Not apples to oranges, but what was done in past years. The recommendation to use the high dose trivalent vaccine was based upon previous data that found the higher dose resulted in an NNT to prevent a case of influenza was 200 (N Engl J Med 2014; 371:635-645; DOI: 10.1056/NEJMoa1315727) and in an observational study, where there was a lowered rate of hospital admissions (Lancet Respir Med 2017; 5: 738–46).

This year, both the standard and high dose will be quadrivalent. Whatever this paper does tells us, it does NOT apply to this year’s flu season.

The heart of this paper lives in the authors’ conflicts of interests; the list is enormous, filled with researchers who work for Sanofi, the people that make the high dose quadrivalent vaccine.

There is no clear data on what to offer patients 65 and older this year. And since we have no idea about COVID and lock downs this flu season, it may not matter much. Until we know more, do what you think is best for you patients. If past data is to be considered, the benefit of the higher dose vaccine is small, at best, and has a high adverse event risk.

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Contributed by Frank J. Domino, MD, September 8, 2021