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In a population-based cohort study of adolescents and adults in Denmark who received two doses of the same mRNA vaccine against COVID, the risk of myocarditis or myopericarditis within 28 days was rare, as has been reported from other recent passive surveillance studies and case series.
The risk of this outcome, though rare, was significantly higher in both males and females who were vaccinated with the mRNA-1273 (Moderna) vaccine compared with unvaccinated individuals.
However, “surprisingly,” the risk of this adverse effect after vaccination with the BNT162b2 (Pfizer-BioNTech) vaccine was significantly higher only in females.
In addition, the rates of myocarditis or myopericarditis after mRNA vaccination in this population were lower than those reported by researchers in the United States and Israel.
The study, with lead author Anders Husby, MD, PhD, Department of Epidemiology and Biostatistics, Imperial College, London, England, and Statens Serum Institute, Copenhagen, Denmark, was published online December 16 in BMJ.
It “confirms what is already known about vaccine associated myocarditis — that it is rare, but it exists,” Walid F. Gellad, MD, MPH, summarizes in an editorial that accompanied the study.
Population-based data, which has less likelihood of bias compared to surveillance data or case reports, had been missing until now, notes Gellad, professor of medicine and director of the Center for Pharmaceutical Policy & Prescribing, University of Pittsburgh, Pennsylvania.
“The mRNA vaccines against COVID-19 are remarkably effective and provide tremendous benefit to recipients,” he stresses, and “the risks of myocarditis or myopericarditis are low and must be balanced against these many benefits.”
“Population-based studies such as this one are vital for ensuring this proper balancing, and for identifying ways to maintain the benefits of vaccination while reducing the risks,” he writes.
Similarly, the researchers note that “the clinical outcomes after myocarditis or myopericarditis events were predominantly mild, providing evidence to support the overall safety of SARS-CoV-2 mRNA vaccines.”
“The individual and societal benefits of vaccination still clearly outweigh the risks, especially when the alternative is infection, which in itself may cause myocarditis, severe COVID-19 disease, and long COVID,” senior author Anders Hviid, PhD, professor of epidemiology, Statens Serum Institute, told theheart.org | Medscape Cardiology in an email.
“Given the worldwide spread of the highly contagious SARS-CoV-2 Delta and Omicron variants, future infection is the undesirable alternative to vaccination against SARS-CoV-2,” the researchers caution.
“Taken together with the potential long-term sequelae of even mild SARS-CoV-2 infection, and with the risk of multisystem inflammatory syndrome among adolescents (which is associated with severe morbidity),” they conclude, “our finding of a low absolute risk of myocarditis or myopericarditis with BNT162b2 or mRNA-1273 vaccination supports the overall benefits of such vaccination on an individual, societal, and global level.”
Registry Data From Denmark
Myocarditis and myopericarditis are rare and are usually triggered by a viral, bacterial, or fungal infection, but vaccination with an mRNA vaccine, especially the second dose, has also been associated with a greater risk of this adverse effect, which, in serious cases, can cause heart failure or death.
The researchers reviewed registry data from all 5 million residents in Denmark age 12 and older from October 2020 to October 2021, to determine the rate of myocarditis and myopericarditis within 28 days after receipt of an mRNA vaccine against COVID.
The two doses were given about 33 days apart.
The main analysis included 3.5 million individuals who had received BNT162b2 vaccine and 500,000 individuals who had received mRNA-1273 vaccine.
The researchers defined myocarditis or myopericarditis as the combined outcome of a hospital diagnosis of this inflammation of the heart muscle or heart muscle lining, respectively, plus increased troponin levels and a hospital stay longer than 24 hours.
During follow-up, 269 individuals had myocarditis or myopericarditis (40% were 12-39 years old and 73% were male).
In general, the rate of myocarditis or myopericarditis was about three- to fourfold higher after vaccination with mRNA-1273 than with BNT162b2.
The absolute number of events was low and clinical outcomes among vaccinated people with myocarditis or myopericarditis were predominantly mild.
For the Moderna mRNA-1273 vaccine against COVID:
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Of the 498,814 individuals who received the Moderna vaccine, 21 developed myocarditis or myopericarditis, giving an absolute rate of 4.2 events per 100,000 vaccinated individuals.
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The risk was increased in both male and female individuals.
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Among 12- to 39-year-olds, the adjusted hazard ratio (HR) — after adjusting for age, sex, vaccine priority group, season, and clinical comorbidities — was 5.24, for an absolute rate of 5.7 events per 100,000 vaccinated individuals.
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Among the youngest individuals, age 12 to 17, the absolute rate of this risk was only 1.0 event per 100,000 vaccinated individuals. In comparison, the estimated rate of multisystem inflammatory syndrome in this age group among individuals who have a positive serological test for COVID infection is 27 events per 100,000 individuals.
For the Pfizer-BioNTech BNT162b2 vaccine against COVID:
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Of the 3,482,295 individuals who received the Pfizer-BioNTech vaccine, 48 developed myocarditis or myopericarditis, for an overall absolute rate of 1.4 events per 100,000 vaccinated individuals.
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Women, but not men, had a significantly increased risk of this outcome compared with unvaccinated women (adjusted HR, 3.73; 95% CI, 1.82 – 7.65), for an absolute rate of 1.3 events per 100,000 vaccinated individuals.
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Among 12- to 39-year-olds, the adjusted HR of this outcome was 1.48 and the absolute rate was 1.6 events per 100,000 vaccinated individuals.
“In perhaps the most surprising result, the [BNT162b2] vaccine was associated with myocarditis or myopericarditis only in female, not male, participants,” Gellad writes. “That just under half of the cases were in female participants and after the first dose is unexpected, inconsistent with international data, and hard to explain.”
“One of the novel findings was that we also observed an association among women for both vaccines,” Hviid said. “However, the risk of myocarditis in women is lower than in men by a factor of 4, meaning that the risk due to vaccination is still very small.”
The rate of myocarditis following receipt of BNT162b2 or mRNA-1273 vaccines in the current study was lower than the rate reported in studies from Israel and the United States, Gellad also notes.
For example, overall, among 5.1 million Israelis vaccinated with BNT162b2, there were 136 cases of myocarditis within 21 days, or 2.7 per 100,000 (compared with 1.4 per 100,000 in Denmark). The rates of myocarditis were also higher in Israel than in Denmark in young age groups.
This may be due to the wider spacing between the two doses (5 weeks in Denmark vs 3 weeks in the US and Israel), Gellad suggests. Researchers in Canada found a lower rate of myocarditis with longer spacing between doses, and in the United Kingdom, which also extended time between doses, the rate of myocarditis after BNT162b2 vaccination was similarly low: 1 per 100,000.
The rates might also be lower in Denmark because of the strict definition of myocarditis, requiring a hospital stay of at least 24 hours and an increased troponin level, he adds.
“Larger multinational studies and meta-analyses are needed to specify risks within smaller subgroups and the risk of myocarditis or myopericarditis after SARS-CoV-2 infection versus vaccination,” the researchers conclude.
The researchers were supported by a grant from the Lundbeck Foundation. Husby and Hviid have disclosed no relevant financial relationships. The disclosures of the other authors are listed in the article.
BMJ. 2021;375:e068665, n3090. Full text, Editorial
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