Karlstad O, Hovi P, Husby A, et al. SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents. JAMA Cardiol. 2022 Apr 20. pii: 2791253. doi: 10.1001/jamacardio.2022.0583. (Original study)

Importance: Reports of myocarditis after SARS-CoV-2 messenger RNA (mRNA) vaccination have emerged.

Objective: To evaluate the risks of myocarditis and pericarditis following SARS-CoV-2 vaccination by vaccine product, vaccination dose number, sex, and age.

Design, Setting, and Participants: Four cohort studies were conducted according to a common protocol, and the results were combined using meta-analysis. Participants were 23?122?522 residents aged 12 years or older. They were followed up from December 27, 2020, until incident myocarditis or pericarditis, censoring, or study end (October 5, 2021). Data on SARS-CoV-2 vaccinations, hospital diagnoses of myocarditis or pericarditis, and covariates for the participants were obtained from linked nationwide health registers in Denmark, Finland, Norway, and Sweden.

Exposures: The 28-day risk periods after administration date of the first and second doses of a SARS-CoV-2 vaccine, including BNT162b2, mRNA-1273, and AZD1222 or combinations thereof. A homologous schedule was defined as receiving the same vaccine type for doses 1 and 2.

Main Outcomes and Measures: Incident outcome events were defined as the date of first inpatient hospital admission based on primary or secondary discharge diagnosis for myocarditis or pericarditis from December 27, 2020, onward. Secondary outcome was myocarditis or pericarditis combined from either inpatient or outpatient hospital care. Poisson regression yielded adjusted incidence rate ratios (IRRs) and excess rates with 95% CIs, comparing rates of myocarditis or pericarditis in the 28-day period following vaccination with rates among unvaccinated individuals.

Results: Among 23?122?522 Nordic residents (81% vaccinated by study end; 50.2% female), 1077 incident myocarditis events and 1149 incident pericarditis events were identified. Within the 28-day period, for males and females 12 years or older combined who received a homologous schedule, the second dose was associated with higher risk of myocarditis, with adjusted IRRs of 1.75 (95% CI, 1.43-2.14) for BNT162b2 and 6.57 (95% CI, 4.64-9.28) for mRNA-1273. Among males 16 to 24 years of age, adjusted IRRs were 5.31 (95% CI, 3.68-7.68) for a second dose of BNT162b2 and 13.83 (95% CI, 8.08-23.68) for a second dose of mRNA-1273, and numbers of excess events were 5.55 (95% CI, 3.70-7.39) events per 100?000 vaccinees after the second dose of BNT162b2 and 18.39 (9.05-27.72) events per 100?000 vaccinees after the second dose of mRNA-1273. Estimates for pericarditis were similar.

Conclusions and Relevance: Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100?000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100?000 vaccinees after mRNA-1273. This risk should be balanced against the benefits of protecting against severe COVID-19 disease.

Discipline Area Score
Cardiology 7 / 7
Public Health 6 / 7
Internal Medicine 6 / 7
Infectious Disease 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Comments from MORE raters

Cardiology rater

The risk for myocarditis was higher within 28 days of vaccination with both BNT162b2 and mRNA-1273 compared with being unvaccinated, and higher after the second dose of vaccine than the first dose. We are writing a report on this (COVID and heart) for our national medical journal in Finland.

Cardiology rater

This is the best available population data on the incidence of myocarditis associated with mRNA COVID vaccines.

Infectious Disease rater

This study is likely the best we will have in terms of quantitating the risk for myocarditis and pericarditis following mRNA vaccine for COVID-19. I see no major flaw. The incidence of this complication is low, so it is probably necessary to have a registry of over 10,000,000 people to define the absolute risk and to do the necessary sub-group analysis. The interpretation is important for public health groups to frame. Could there be ethnic differences in other countries? Could there have been a higher rate of looking for cardiac problems in view of the prior vaccination? Maybe. But this seems unlikely to be the driver for the excess risk. Subsequent mRNA vaccines can be studied prospectively to see whether the method of delivery or the antigen(s) delivered increase this risk.

Infectious Disease rater

This large study confirms previous findings that myocarditis and pericarditis are increased in young males after receiving mRNA COVID vaccines. It also confirms that myocarditis is increased after a diagnosis of COVID infection in young males.

Internal Medicine rater

From experience on our Cardiac Hospitalist Service, there is likely also increased risk for myocarditis from having Covid, although I have no data to support this.

Internal Medicine rater

In this very large database study of Nordic countries, an excess of myocarditis and pericarditis cases were found in patients receiving COVID-19 vaccinations, especially in young males. This finding has been identified before, but their database suggests higher rates than were previously discovered. It also describes higher rates after a 2nd dose, which suggest a legitimate immune mechanism, and also higher rates after Moderna compared with Pfizer vaccines. Young non-immunosuppressed patients are at very low likelihood to die of COVID-19; however, they seem to bear a larger share of the burden of this unusual side effect. This factor will be have to be weighed in future booster recommendations for this demographic.

Public Health rater

Large cohort study including >23 million participants from 4 Nordic countries. This confirms signals seen in other jurisdictions, including Ontario about increased risk for myocarditis after first and second doses, more pronounced in males 16-24 years. Risk for myocarditis should be weighed against benefit in preventing severe COVID-19, particularly when prevalence of SARS-CoV-2 is high in the community.

Public Health rater

Consistent findings about the vaccine-associated risk for myocarditis (increased in younger patients after 2nd dose with mRNA-1273) in a population study of 4 countries. What is missing is the benefit side of the calculus.
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