Key Points
Question
What is the long-term prognosis of myocarditis after COVID-19 mRNA vaccination and do clinical outcomes and medical management differ from myocarditis of other origins?
Finding
In this nationwide cohort study including 4635 patients hospitalized for myocarditis in France during the first 1.5 years after COVID-19 vaccination, the 558 individuals with postvaccine myocarditis had less severe cardiovascular events than those with myocarditis of other origins at 18 months of follow-up. However, affected patients, mainly healthy young men, may require medical management up to several months after hospital discharge.
Meaning
These elements should be taken into account for ongoing and future mRNA vaccine recommendations.
Abstract
Importance
Although patients with myocarditis after COVID-19 mRNA vaccination appear to have a good prognosis near hospital discharge, their longer-term prognosis and management remain unknown.
Objective
To study the cardiovascular complications of post–COVID-19 mRNA vaccination myocarditis and other types of myocarditis during an 18-month follow-up, as well as disease management based on a study of the frequency of medical procedures and drug prescriptions.
Design, Setting, and Participants
In this cohort study based on the French National Health Data System, all individuals aged 12 to 49 years hospitalized for myocarditis in France between December 27, 2020, and June 30, 2022, were identified.
Exposure
Individuals were categorized as having postvaccine myocarditis (within 7 days after COVID-19 mRNA vaccine), post–COVID-19 myocarditis (within 30 days of SARS-CoV-2 infection), or conventional myocarditis.
Main Outcomes and Measures
The occurrence of clinical outcomes (hospital readmission for myopericarditis, other cardiovascular events, all-cause death, and a composite outcome of these events) over the 18 months following hospital admission were analyzed using weighted Cox models to standardize the comparisons with the conventional myocarditis group. Also, medical management after hospital discharge was longitudinally assessed using generalized estimated equation models.
Results
In total, 4635 individuals were hospitalized for myocarditis: 558 with postvaccine myocarditis, 298 with post–COVID-19 myocarditis, and 3779 with conventional myocarditis. Patients with postvaccine myocarditis were younger than those with post–COVID-19 and conventional myocarditis (mean [SD] age of 25.9 [8.6], 31.0 [10.9], and 28.3 [9.4] years, respectively) and were more frequently men (84%, 67%, and 79%). Patients with postvaccine myocarditis had a lower standardized incidence of the composite clinical outcome than those with conventional myocarditis (32/558 vs 497/3779 events; weighted hazard ratio, 0.55 [95% CI, 0.36-0.86]), whereas individuals with post–COVID-19 myocarditis had similar results (36/298 events; weighted hazard ratio, 1.04 [95% CI, 0.70-1.52]). The standardized frequency of medical procedures and drugs prescribed in patients with postvaccine myocarditis or post–COVID-19 myocarditis followed a similar trend in the 18 months following hospital discharge to that of patients with conventional myocarditis.
Conclusions and Relevance
Patients with post–COVID-19 mRNA vaccination myocarditis, contrary to those with post–COVID-19 myocarditis, show a lower frequency of cardiovascular complications than those with conventional myocarditis at 18 months. However, affected patients, mainly healthy young men, may require medical management up to several months after hospital discharge.
This cohort study examines cardiovascular complications of postvaccine and other types of myocarditis (ie, post–COVID-19 and conventional myocarditis) during 18-month follow-up.
Introduction
Cases of myocarditis have been broadly reported following vaccination with the COVID-19 mRNA BNT162b2 and mRNA-1273 vaccines.1 Several epidemiological studies2 confirmed an increased risk of myocarditis shortly after vaccination, predominantly in young adults and after the second dose. In a previous case-control study of individuals aged 12 to 50 years,3 Le Vu et al reported an increased risk of myocarditis during the first week following vaccination compared with unvaccinated individuals, reaching a 30-fold–higher risk for the second dose of the mRNA-1273 vaccine. Also, SARS-CoV-2 infection occurring in the previous month was associated with a risk of myocarditis,3 in accordance with the literature.4,5
Although vaccination resulted in a significant decrease in hospitalization and mortality from COVID-19,6,7 it is crucial to evaluate the consequences of postvaccine myocarditis, particularly in young people, who are less likely to have serious illness after SARS-CoV-2 infection and could thus be less inclined toward vaccination. Studies have shown that the prognosis at hospital discharge after postvaccine myocarditis was generally favorable,8,9,10,11 with short hospital stays and seldom cases of death. Only 1 comparative study, based on the populations of 4 Nordic countries, had a large sample size and a 3-month posthospitalization follow-up. Results showed postvaccine myocarditis to be associated with a lower risk of heart failure within 90 days after hospital admission than myocarditis unrelated to COVID-19 vaccination or SARS-CoV-2 infection (ie, conventional myocarditis).12 However, most of these studies had a short or no posthospitalization follow-up and did not address the management of myocarditis over time or its long-term complications.
This study aimed to examine the cardiovascular complications of postvaccine myocarditis and other types of myocarditis (ie, post–COVID-19 and conventional myocarditis) during an 18-month follow-up, as well as disease management at discharge based on a study of the frequency of medical procedures and drug prescriptions.
Methods
Data Sources
This cohort study used data from the French national hospital discharge database (PMSI), coupled with the French national COVID-19 vaccination database (VAC-SI), the SARS-COV-2 diagnosis testing database (SI-DEP), and the National Health Data System (SNDS), which covers the entire population of France (67 million residents). Each person is anonymously identified by a unique, lifelong number. Since 2006, the SNDS has recorded all reimbursement data for both outpatient care (including drugs, imaging, and laboratory tests) and inpatient care (including diagnoses and procedures performed) from the PMSI, as well as fully reimbursed health expenditures for patients with long-term diseases, such as cancer and diabetes. These data are pseudonymized. Therefore, no informed consent is required to perform this study, nor approval from an ethics committee/institutional review board. The SNDS has been extensively used to conduct real-life pharmacoepidemiological studies, including during the COVID-19 pandemic and vaccination periods.3,13,14,15,16
Design, Study Population, and End Points
Regulatory approval and ethical aspects are available in the eMethods in Supplement 1). The cohort included all individuals aged 12 to 49 years who had a main or related diagnosis of myocarditis (defined by International Classification of Diseases and Related Health Problems, 10th Revision codes) from inpatient hospital care from December 27, 2020, to June 30, 2022 (eMethods in Supplement 1).
Individuals admitted to the hospital for myocarditis within 7 days after receipt of any dose of a COVID-19 mRNA vaccine were categorized as having postvaccine myocarditis.3 Individuals admitted to the hospital for myocarditis within 30 days of SARS-CoV-2 infection and who did not receive an mRNA vaccination within the preceding 7 days were categorized as having post–COVID-19 myocarditis3 (eMethods in Supplement 1). Only 7 individuals, for whom there was a history of both COVID-19 mRNA vaccination within 7 days and COVID-19 within 30 days, were excluded because they could be classified in either group. The remaining cases of myocarditis were categorized as conventional myocarditis.
Clinical outcomes of hospital readmission for myopericarditis with at least 1 overnight stay, the occurrence of another cardiovascular event (code details in the eMethods in Supplement 1), all-cause hospitalization with at least 1 overnight stay, and all-cause death during the follow-up were identified. Two composite clinical outcomes were also defined: the first by the occurrence of rehospitalization for myopericarditis, another cardiovascular event, or death from any cause and the second by adding hospitalization for any reason to the first. All individuals were followed up for 18 months from the date of initial hospital admission (index date) for myocarditis. Time to event for individual cardiovascular outcomes was censored at the time of occurrence of the event of interest, death from any cause, or the end of the study on December 31, 2023, whichever occurred first. Time to event for the composite outcomes was censored at the first occurrence of any outcome of interest, death from any cause, or the end of the study on December 31, 2023, whichever occurred first.
Medical procedures and drugs administered at 3 months and between 3 and 6 months, 6 and 12 months, and 12 and 18 months were analyzed. Follow-up lasted 18 months from the date of initial hospital discharge for myocarditis and was complete for more than 99% of the population studied (eMethods in Supplement 1). Reimbursement for diagnostic procedures and specific drugs was also identified (eTable 9 in Supplement 1).
Details of sociodemographic characteristics, chronic diseases, and comorbidities at baseline are available in the eMethods in Supplement 1.
Statistical Analysis
The characteristics, clinical outcomes, medical procedures, and drugs prescribed for patients with postvaccine myocarditis are described overall and by the vaccine dose involved (first, second, or third dose).
Cox regression models were used to compare the incidence of each clinical outcome and the 2 composite outcomes during the 18-month follow-up between postvaccine myocarditis, post–COVID-19 myocarditis, and conventional myocarditis. These models were weighted after modeling the probability of the myocarditis type, as described below, to standardize incidences using the conventional myocarditis group as the target group based on sociodemographic characteristics and comorbidities presented in Table 1 and Table 2. The individual probability of developing 1 of the 3 types of myocarditis was estimated using a multinomial multivariable logistic regression model17 and was used to calculate the weights. This weighting was set at 1 for patients in the target group and calculated as a ratio between the probability of the target group and that of the actual group for the other groups.18 We provided 95% CIs from 1000 bootstrap resamples,19 except where the number of events was less than 5 due to instability of estimates.
Table 1. Baseline Characteristics of Patients With Post–COVID-19 mRNA Vaccination Myocarditis .
| No. (%) | Absolute standardized differencea | |||||
|---|---|---|---|---|---|---|
| Postvaccine myocarditis (n = 558) | Postvaccine myocarditis after dose 1 (n = 74) | Postvaccine myocarditis after dose 2 (n = 376) | Postvaccine myocarditis after dose 3 (n = 108) | Dose 1 vs dose 2 | Dose 3 vs dose 2 | |
| Length of hospital stay, d | ||||||
| Mean (SD) | 4.1 (2.4) | 3.7 (1.7) | 4.2 (2.6) | 3.9 (2.3) | −0.223 | −0.109 |
| Median (IQR) | 4 (3 to 5) | 4 (3 to 5) | 4 (3 to 5) | 4 (3 to 5) | ||
| Age, mean (SD), y | 25.9 (8.6) | 27.7 (8.8) | 24.9 (8.4) | 27.8 (8.4) | 0.323 | 0.339 |
| Age group, y | 0.369 | 0.480 | ||||
| 12-17 | 61 (10.9) | 7 (9.5) | 52 (13.8) | 2 (1.9) | −0.137 | −0.457 |
| 18-24 | 247 (44.3) | 27 (36.5) | 169 (44.9) | 51 (47.2) | −0.173 | 0.046 |
| 25-29 | 86 (15.4) | 9 (12.2) | 59 (15.7) | 18 (16.7) | −0.102 | 0.026 |
| 30-39 | 114 (20.4) | 24 (32.4) | 67 (17.8) | 23 (21.3) | 0.342 | 0.088 |
| 40-49 | 50 (9.0) | 7 (9.5) | 29 (7.7) | 14 (13.0) | 0.062 | 0.173 |
| Sex | −0.080 | −0.174 | ||||
| Male | 467 (84) | 61 (82) | 321 (85) | 85 (79) | −0.080 | −0.174 |
| Female | 91 (16) | 13 (18) | 55 (15) | 23 (21) | 0.080 | 0.174 |
| Region | 0.565 | 0.247 | ||||
| Auvergne-Rhône-Alpes | 77 (13.8) | 9 (12.2) | 53 (14.1) | 15 (13.9) | −0.057 | −0.006 |
| Ile de France | 81 (14.5) | 18 (24.3) | 48 (12.8) | 15 (13.9) | 0.301 | 0.033 |
| Occitanie | 61 (10.9) | 9 (12.2) | 42 (11.2) | 10 (9.3) | 0.031 | −0.063 |
| Nouvelle-Aquitaine | 58 (10.4) | 6 (8.1) | 41 (10.9) | 11 (10.2) | −0.095 | −0.023 |
| Grand Est | 52 (9.3) | 1 (1.4) | 39 (10.4) | 12 (11.1) | −0.391 | 0.024 |
| Hauts-de-France | 50 (9.0) | 8 (10.8) | 28 (7.4) | 14 (13.0) | 0.117 | 0.183 |
| Provence-Alpes-Côte d’Azur | 38 (6.8) | 6 (8.1) | 25 (6.6) | 7 (6.5) | 0.056 | −0.007 |
| Pays de la Loire | 31 (5.6) | 4 (5.4) | 22 (5.9) | 5 (4.6) | −0.019 | −0.055 |
| Bourgogne-Franche-Comté | 29 (5.2) | 2 (2.7) | 22 (5.9) | 5 (4.6) | −0.156 | −0.055 |
| Normandie | 28 (5.0) | 4 (5.4) | 19 (5.1) | 5 (4.6) | 0.016 | −0.020 |
| Centre-Val-de-Loire | 23 (4.1) | 2 (2.7) | 18 (4.8) | 3 (2.8) | −0.110 | −0.105 |
| Bretagne | 24 (4.3) | 3 (4.1) | 16 (4.3) | 5 (4.6) | −0.010 | 0.018 |
| Overseas territories | 4 (0.7) | 1 (1.4) | 2 (0.5) | 1 (0.9) | 0.085 | 0.046 |
| Corse | 2 (0.4) | 1 (1.4) | 1 (0.3) | 0 | 0.121 | −0.073 |
| Social Deprivation Index (quintile) | 0.230 | 0.361 | ||||
| Nonmissing | 553 (99.1) | 74 (100.0) | 374 (99.5) | 105 (97.2) | 0.103 | −0.177 |
| 1 (Least deprived) | 105 (19.0) | 17 (23.0) | 63 (16.8) | 25 (23.8) | 0.156 | 0.160 |
| 2 | 109 (19.7) | 13 (17.6) | 81 (21.7) | 15 (14.3) | −0.100 | −0.201 |
| 3 | 122 (22.1) | 16 (21.6) | 86 (23.0) | 20 (19.0) | −0.030 | −0.108 |
| 4 | 109 (19.7) | 11 (14.9) | 70 (18.7) | 28 (26.7) | −0.101 | 0.176 |
| 5 (Most deprived) | 108 (19.5) | 17 (23.0) | 74 (19.8) | 17 (16.2) | 0.080 | −0.103 |
| Time since last vaccination, median (IQR), d | 3 (3 to 4) | 4 (3 to 5) | 3 (3 to 4) | 4 (3 to 4) | ||
| Lifestyle habits | ||||||
| Opioid addiction | 2 (0.4) | 0 | 1 (0.3) | 1 (0.9) | −0.073 | 0.086 |
| Smoking | 30 (5.4) | 4 (5.4) | 23 (6.1) | 3 (2.8) | −0.031 | −0.163 |
| Alcohol-related disorders | 14 (2.5) | 0 | 9 (2.4) | 5 (4.6) | −0.221 | 0.122 |
| Comorbidities | ||||||
| Cardiometabolic | ||||||
| History of myocarditis | 14 (2.5) | 4 (5.4) | 8 (2.1) | 2 (1.9) | 0.173 | −0.020 |
| Antihypertensive treatments | 10 (1.8) | 1 (1.4) | 5 (1.3) | 4 (3.7) | 0.002 | 0.152 |
| Coronary heart disease | 6 (1.1) | 2 (2.7) | 4 (1.1) | 0 | 0.121 | −0.147 |
| Heart failure | 3 (0.5) | 1 (1.4) | 2 (0.5) | 0 | 0.085 | −0.103 |
| Diabetes | 4 (0.7) | 0 | 1 (0.3) | 3 (2.8) | −0.073 | 0.206 |
| Dyslipidemia and lipid-lowering treatments | 6 (1.1) | 2 (2.7) | 1 (0.3) | 3 (2.8) | 0.203 | 0.206 |
| Obliterative arteriopathy of the lower limbs | 1 (0.2) | 0 | 1 (0.3) | 0 | −0.073 | −0.073 |
| Heart rhythm and conduction disorders | 3 (0.5) | 1 (1.4) | 1 (0.3) | 1 (0.9) | 0.121 | 0.089 |
| Stroke | 1 (0.2) | 1 (1.4) | 0 | 0 | 0.166 | |
| Respiratory | ||||||
| Chronic respiratory diseases | 23 (4.1) | 4 (5.4) | 11 (2.9) | 8 (7.4) | 0.124 | 0.204 |
| Cancer | ||||||
| Cancer (under surveillance) | 4 (0.7) | 0 | 3 (0.8) | 1 (0.9) | −0.127 | 0.014 |
| Other | ||||||
| Anti-infective treatment within the last 30 d | 30 (5.4) | 4 (5.4) | 21 (5.6) | 5 (4.6) | −0.008 | −0.043 |
| Anxiolytics | 15 (2.7) | 1 (1.4) | 12 (3.2) | 2 (1.9) | −0.124 | −0.086 |
| Antidepressants | 14 (2.5) | 3 (4.1) | 10 (2.7) | 1 (0.9) | 0.077 | −0.131 |
| Autoimmune diseases | 5 (0.9) | 1 (1.4) | 4 (1.1) | 0 | 0.026 | −0.147 |
| Hypnotics | 2 (0.4) | 0 | 2 (0.5) | 0 | −0.103 | −0.103 |
The absolute standardized difference was calculated as the difference between groups in means (continuous variables) or frequency (categorical variables) divided by the SD of the target group (dose 2).
Table 2. Baseline Characteristics of Patients With Myocarditis Identified During the COVID-19 Pandemic Period (December 27, 2020, to June 30, 2022)a.
| Postvaccine myocarditis (n = 558) | Post–COVID-19 myocarditis (n = 298) | Conventional myocarditis (n = 3779) | Absolute standardized differenceb | ||
|---|---|---|---|---|---|
| Postvaccine vs conventional | Post–COVID-19 vs conventional | ||||
| Length of hospital stay, d | |||||
| Mean (SD) | 4.1 (2.4) | 8.2 (14.3) | 4.9 (6.1) | −0.180 | 0.295 |
| Median (IQR) | 4 (3 to 5) | 5 (3 to 8) | 4 (3 to 6) | ||
| Age, mean (SD), y | 25.9 (8.6) | 31.0 (10.9) | 28.3 (9.4) | −0.271 | 0.265 |
| Age group, y | 0.293 | 0.424 | |||
| 12-17 | 61 (10.9) | 42 (14.1) | 390 (10.3) | 0.020 | 0.115 |
| 18-24 | 247 (44.3) | 57 (19.1) | 1221 (32.3) | 0.248 | −0.305 |
| 25-29 | 86 (15.4) | 31 (10.4) | 644 (17.0) | −0.044 | −0.194 |
| 30-39 | 114 (20.4) | 92 (30.9) | 932 (24.7) | −0.101 | 0.139 |
| 40-49 | 50 (9.0) | 76 (25.5) | 592 (15.7) | −0.205 | 0.245 |
| Sex | 0.131 | −0.267 | |||
| Male | 467 (84) | 199 (67) | 2969 (79) | 0.131 | −0.267 |
| Female | 91 (16) | 99 (33) | 810 (21) | −0.131 | 0.267 |
| Region | 0.269 | 0.357 | |||
| Ile de France | 81 (14.5) | 77 (25.8) | 831 (22.0) | −0.194 | 0.090 |
| Auvergne-Rhône-Alpes | 77 (13.8) | 33 (11.1) | 469 (12.4) | 0.041 | −0.042 |
| Occitanie | 61 (10.9) | 20 (6.7) | 346 (9.2) | 0.059 | −0.091 |
| Provence-Alpes-Côte d’Azur | 38 (6.8) | 24 (8.1) | 326 (8.6) | −0.068 | −0.021 |
| Nouvelle-Aquitaine | 58 (10.4) | 23 (7.7) | 302 (8.0) | 0.083 | −0.010 |
| Hauts-de-France | 50 (9.0) | 23 (7.7) | 286 (7.6) | 0.051 | 0.006 |
| Grand Est | 52 (9.3) | 18 (6.0) | 257 (6.8) | 0.093 | −0.031 |
| Pays de la Loire | 31 (5.6) | 12 (4.0) | 221 (5.8) | −0.013 | −0.084 |
| Normandie | 28 (5.0) | 16 (5.4) | 199 (5.3) | −0.011 | 0.005 |
| Centre-Val-de-Loire | 23 (4.1) | 9 (3.0) | 172 (4.6) | −0.021 | −0.080 |
| Bourgogne-Franche-Comté | 29 (5.2) | 8 (2.7) | 151 (4.0) | 0.057 | −0.073 |
| Bretagne | 24 (4.3) | 8 (2.7) | 130 (3.4) | 0.045 | −0.044 |
| Overseas territories | 4 (0.7) | 24 (8.1) | 61 (1.6) | −0.084 | 0.304 |
| Corse | 2 (0.4) | 3 (1.0) | 28 (0.7) | −0.052 | 0.029 |
| Social Deprivation Index (quintile) | 0.107 | 0.195 | |||
| Nonmissing | 553 (99.1) | 291 (97.7) | 3713 (98.3) | 0.074 | −0.043 |
| 1 (Least deprived) | 105 (19.0) | 58 (19.9) | 770 (20.7) | −0.039 | −0.023 |
| 2 | 109 (19.7) | 43 (14.8) | 775 (20.9) | −0.024 | −0.161 |
| 3 | 122 (22.1) | 57 (19.6) | 727 (19.6) | 0.065 | −0.003 |
| 4 | 109 (19.7) | 57 (19.6) | 691 (18.6) | 0.032 | 0.022 |
| 5 (Most deprived) | 108 (19.5) | 76 (26.1) | 750 (20.2) | −0.012 | 0.135 |
| Time since last vaccination, median (IQR), d | 3 (3 to 4) | 127 (72 to 180) | 94 (43 to 147) | ||
| No. of COVID-19 vaccination at the index date | 1.372 | 0.180 | |||
| 0 | 0 | 160 (53.7) | 1804 (47.7) | −1.352 | 0.119 |
| 1 | 74 (13.3) | 27 (9.1) | 360 (9.5) | 0.118 | −0.016 |
| 2 | 376 (67.4) | 69 (23.2) | 1141 (30.2) | 0.802 | −0.160 |
| 3 | 108 (19.4) | 41 (13.8) | 473 (12.5) | 0.188 | 0.038 |
| 4 | 0 | 1 (0.3) | 1 (0.0) | −0.023 | 0.073 |
| Lifestyle habits | |||||
| Opioid addiction | 2 (0.4) | 2 (0.7) | 24 (0.6) | −0.039 | 0.004 |
| Smoking | 30 (5.4) | 33 (11.1) | 278 (7.4) | −0.081 | 0.129 |
| Alcohol-related disorders | 14 (2.5) | 9 (3.0) | 71 (1.9) | 0.043 | 0.074 |
| Comorbidities | |||||
| Cardiometabolic | |||||
| History of myocarditis | 14 (2.5) | 9 (3.0) | 247 (6.5) | −0.195 | −0.165 |
| Antihypertensive treatments | 10 (1.8) | 21 (7.0) | 239 (6.3) | −0.231 | 0.029 |
| Heart rhythm and conduction disorders | 3 (0.5) | 14 (4.7) | 138 (3.7) | −0.219 | 0.052 |
| Coronary heart disease | 6 (1.1) | 10 (3.4) | 132 (3.5) | −0.162 | −0.008 |
| Heart failure | 3 (0.5) | 14 (4.7) | 84 (2.2) | −0.145 | 0.136 |
| Diabetes | 4 (0.7) | 9 (3.0) | 68 (1.8) | −0.097 | 0.080 |
| Dyslipidemia and lipid-lowering treatments | 6 (1.1) | 10 (3.4) | 42 (1.1) | −0.003 | 0.152 |
| Heart valve diseases | 0 | 1 (0.3) | 28 (0.7) | −0.122 | −0.055 |
| Stroke | 1 (0.2) | 3 (1.0) | 22 (0.6) | −0.065 | 0.048 |
| Obliterative arteriopathy of the lower limbs | 1 (0.2) | 1 (0.3) | 3 (0.1) | 0.028 | 0.056 |
| Respiratory | |||||
| Chronic respiratory diseases | 23 (4.1) | 24 (8.1) | 240 (6.4) | −0.100 | 0.066 |
| Pulmonary embolism | 0 | 0 | 11 (0.3) | −0.076 | −0.076 |
| Cancer | |||||
| Cancer (active) | 0 | 0 | 53 (1.4) | −0.169 | −0.169 |
| Cancer (under surveillance) | 4 (0.7) | 2 (0.7) | 16 (0.4) | 0.039 | 0.034 |
| Other | |||||
| Anti-infective treatment within the last 30 d | 30 (5.4) | 69 (23.2) | 535 (14.2) | −0.299 | 0.233 |
| Autoimmune diseases | 5 (0.9) | 15 (5.0) | 142 (3.8) | −0.191 | 0.062 |
| Antidepressants | 14 (2.5) | 11 (3.7) | 119 (3.1) | −0.039 | 0.030 |
| Anxiolytics | 15 (2.7) | 12 (4.0) | 114 (3.0) | −0.020 | 0.055 |
| Hypnotics | 2 (0.4) | 7 (2.3) | 33 (0.9) | −0.066 | 0.117 |
| Sarcoidosis | 0 | 0 | 15 (0.4) | −0.089 | −0.089 |
| Long-term dialysis | 0 | 0 | 1 (<0.01) | −0.023 | −0.023 |
| Kidney transplant | 0 | 1 (0.3) | 0 | 0 | 0.082 |
Seven individuals, for whom there was a history of both COVID-19 mRNA vaccination within 7 days and COVID-19 within 30 days, were excluded because they could be classified in either group.
The absolute standardized difference was calculated as the difference between groups in means (continuous variables) or frequency (categorical variables) divided by the SD of the target group (conventional myocarditis).
Medical procedures and drugs administered during the 18-month follow-up period after hospital discharge for each myocarditis group were reported using generalized estimating equations to account for multiple observations per patient using an exchangeable covariance matrix, which assumes the same correlation between the 4 periods (before 3 months, 3 to 6 months, 6 to 12 months, and 12 to 18 months). Generalized estimating equation models were weighted with the same weight calculation method as described above.
Sensitivity analyses were performed to compare the standardized incidence of clinical outcomes between the myocarditis groups by excluding patients with a history of myocarditis, starting follow-up from hospital discharge, defining postvaccine myocarditis within 30 days (instead of 7 days) of vaccine receipt, and using myocarditis identified in 2018 as the target group (details in the eMethods in Supplement 1).
All calculations were performed using SAS Enterprise Guide software, version 8.3 (SAS Institute).
Results
The cohort included 4635 individuals hospitalized for myocarditis during the pandemic period from December 27, 2020, to June 30, 2022: 558 (12%) were categorized as having postvaccine myocarditis, 298 (6%) as having post–COVID-19 myocarditis, and 3779 (82%) as having conventional myocarditis (eFigure in Supplement 1).
Description and Follow-Up of Postvaccine Myocarditis
Most cases of postvaccine myocarditis (n = 376 [67%]) occurred after a second vaccine dose (Table 1). During the initial hospital stay for myocarditis, 1 patient received extracorporeal membrane oxygenation and none of them received a heart transplant. No death occurred during hospitalization. A comparison of the clinical outcomes during the follow-up according to the vaccine dose administered showed no significant differences between doses (eTable 1 in Supplement 1).
Difference of Patient Characteristics by Myocarditis Type
Individuals with postvaccine myocarditis, compared with conventional myocarditis, were younger (mean [SD] age, 25.9 [8.6] vs 28.3 [9.4] years), more frequently male (84% vs 79%), and had a lower frequency of history of cardiometabolic diseases, whereas individuals with post–COVID-19 myocarditis, compared with those with conventional myocarditis, were hospitalized slightly longer (median [IQR] length of stay, 5 [3-8] vs 4 [3-6] days), were older (mean age [SD], 31.0 [10.9] years), were less frequently male (67%), and had more comorbidities (Table 2). Among those with postvaccine myocarditis, 97.5% had no history of myocarditis in the previous 5 years vs 97.0% of those with post–COVID-19 myocarditis and 93.5% of those with conventional myocarditis.
Clinical Outcomes by Myocarditis Type
In the 18 months following hospitalization, 18 of 558 individuals (3.2%) with postvaccine myocarditis, 12 of 298 (4.0%) with post–COVID-19 myocarditis, and 220 of 3779 (5.8%) with conventional myocarditis were rehospitalized for myopericarditis (Table 3). Hospitalization for other cardiovascular events occurred for 15 individuals (2.7%) with postvaccine myocarditis, 22 (7.4%) with post–COVID-19 myocarditis, and 277(7.3%) with conventional myocarditis cases. Death occurred for 1 patient (0.2%) followed-up after postvaccine myocarditis, 4 (1.3%) after post–COVID-19 myocarditis, and 49 (1.3%) after conventional myocarditis, including 0, 4, and 17 deaths, respectively, occurring during the initial hospital stay defining the cohorts.
Table 3. Associations Between Clinical Outcomes and Myocarditis Groups Over 18 Months.
| Outcome | Postvaccine myocarditis (n = 558) | Post–COVID-19 myocarditis (n = 298) | Conventional myocarditis (n = 3779) | |||
|---|---|---|---|---|---|---|
| No. of events (%) | Weighted hazard ratioa | No. of events (%) | Weighted hazard ratioa | No. of events (%) | Weighted hazard ratioa | |
| Rehospitalization for myopericarditis | 18 (3.2) | 0.75 (0.40-1.42) | 12 (4.0) | 1.07 (0.53-2.13) | 220 (5.8) | 1 |
| Cardiovascular event (excluding myopericarditis) | 15 (2.7) | 0.54 (0.27-1.05) | 22 (7.4) | 1.01 (0.62-1.64) | 277 (7.3) | 1 |
| Heart failure, heart rhythm and conduction disorders, cardiomyopathyb | 6 (1.1) | 0.53 (0.07-4.28) | 11 (3.7) | 1.23 (0.58-2.63) | 132 (3.5) | 1 |
| Hospitalization for any cause | 68 (12.2) | 0.69 (0.50-0.94) | 63 (21.1) | 1.04 (0.73-1.48) | 739 (19.6) | 1 |
| Death from any cause | 1 (0.2) | 4 (1.3) | 49 (1.3) | 1 | ||
| Composite outcome 1c | 32 (5.7) | 0.55 (0.36-0.86) | 36 (12.1) | 1.04 (0.70-1.52) | 497 (13.2) | 1 |
| Composite outcome 2c | 75 (13.4) | 0.64 (0.48-0.85) | 76 (25.5) | 1.03 (0.75-1.40) | 874 (23.1) | 1 |
Weighted Cox regression model was used to standardize comparisons according to sociodemographic characteristics and comorbidities of conventional myocarditis described in Table 2. Associations could not be estimated when the number of events was rare (<5).
During the follow-up, infarction occurred in 3/558 patients (0.5%) with postvaccine myocarditis, 4/298 (1.3%) with post–COVID-19 myocarditis, and 56/3779 (1.5%) with conventional myocarditis; cardiac rhythm disorders occurred in 3/558 (0.5%), 5/298 (1.7%), and 52/3779 (1.4%) patients, respectively; and heart failure occurred in 3/558 (0.5%), 7/298 (2.3%), and 45/3779 (1.2%) patients, respectively.
Composite outcome 1: rehospitalization for myopericarditis, cardiovascular event, or death from any cause. Composite outcome 2: rehospitalization for myopericarditis, cardiovascular event, hospitalization for any cause (>1 night stay), or death from any cause.
After standardization on the characteristics of conventional myocarditis cases, postvaccine myocarditis cases presented a lower standardized incidence of rehospitalization for myopericarditis, other cardiovascular events, or all-cause death as a composite outcome (weighted hazard ratio [wHR], 0.55 [95% CI, 0.36-0.86]), while no differences were observed with post–COVID-19 myocarditis (wHR, 1.04 [95% CI, 0.70-1.52]).
Patients with postvaccine myocarditis were less frequently hospitalized for any cause (wHR, 0.69 [95% CI, 0.50-0.94]) than those with conventional myocarditis, while no difference was observed with post–COVID-19 myocarditis. Similar results were found when hospitalization for any cause was added to the composite criterion (wHR for postvaccine myocarditis, 0.64 [95% CI, 0.48-0.85]; wHR for post–COVID-19 myocarditis, 1.03 [95% CI, 0.75-1.40]).
Clinical outcomes by vaccine type for postvaccine myocarditis compared with conventional myocarditis are shown in Table 4. Compared with the conventional myocarditis group, the association observed with the first composite outcome seemed to be stronger in the mRNA-1273 postvaccine myocarditis group than in the BNT162b2 postvaccine group (wHR of 0.24 [95% CI, 0.05-1.18] and 0.68 [95% CI, 0.38-1.22], respectively), but uncertainty on these estimates (ie, large CIs) prevented drawing any firm conclusion.
Table 4. Association Between Clinical Outcomes and Postvaccine and Conventional Myocarditis Over 18 Months According to Vaccine Administered Within the Past 7 Days.
| Outcome | Postvaccine myocarditis | Conventional myocarditis (n = 3779) | ||||
|---|---|---|---|---|---|---|
| Received BNT162b2 vaccine (n = 409) | Received mRNA-1273 vaccine (n = 149) | |||||
| No. of events (%) | Weighted hazard ratioa | No. of events (%) | Weighted hazard ratioa | No. of events (%) | Weighted hazard ratioa | |
| Rehospitalization for myopericarditis | 16 (3.9) | 1.02 (0.46-2.24) | 2 (1.3) | 220 (5.8) | 1 | |
| Cardiovascular event (excluding myopericarditis) | 10 (2.4) | 0.63 (0.25-1.55) | 5 (3.4) | 0.30 (0.02-5.19) | 277 (7.3) | 1 |
| Heart failure, heart rhythm and conduction disorders, cardiomyopathy | 5 (1.2) | 0.74 (0.06-9.83) | 1 (0.7) | 132 (3.5) | 1 | |
| Hospitalization for any cause | 49 (12.0) | 0.74 (0.49-1.13) | 19 (12.8) | 0.44 (0.22-0.89) | 739 (19.6) | 1 |
| Death from any cause | 1 (0.2) | 0 | 49 (1.3) | 1 | ||
| Composite outcome 1b | 25 (6.1) | 0.68 (0.38-1.22) | 7 (4.7) | 0.24 (0.05-1.18) | 497 (13.2) | 1 |
| Composite outcome 2b | 54 (13.2) | 0.69 (0.47-1.02) | 21 (14.1) | 0.43 (0.22-0.83) | 874 (23.1) | 1 |
Weighted Cox regression model was used to standardize comparisons according to sociodemographic characteristics and comorbidities of conventional myocarditis described in Table 2. Associations could not be estimated when the number of events was rare (<5).
Composite outcome 1: rehospitalization for myopericarditis, cardiovascular event, or death from any cause. Composite outcome 2: rehospitalization for myopericarditis, cardiovascular event, hospitalization for any cause (>1 night stay), or death from any cause.
In the sensitivity analyses limited to patients without a history of myocarditis (eTable 2 in Supplement 1) or starting follow-up from hospital discharge (eTable 3 in Supplement 1), similar results to those obtained in the main analysis were found. An age-stratified analysis distinguishing those aged 12 to 29 years from those aged 30 to 49 years also produced similar results (results not shown).
When the definition of postvaccine myocarditis was extended to include patients who received a dose of mRNA vaccine within the previous 30 days (rather than 7), a larger wHR was observed (wHR, 0.84 [95% CI, 0.64-1.09]) for the composite clinical outcome in the postvaccine myocarditis group (eTable 4 in Supplement 1).
A total of 2191 individuals hospitalized for myocarditis were identified in 2018 (during the prepandemic period), categorized as historical control, with similar characteristics at baseline (eTable 5 in Supplement 1) and clinical outcomes during follow-up as those with conventional myocarditis (eTable 6 in Supplement 1). Consistent with the main analysis, patients with postvaccine myocarditis appeared to have a lower standardized incidence of the first composite outcome (wHR, 0.65 [95% CI, 0.40-1.05]) than those with historical myocarditis.
The standardized incidences of the first composite outcome for unvaccinated and vaccinated individuals with post–COVID-19 myocarditis (wHR of 1.06 [95% CI, 0.29-3.86] and 1.23 [95% CI, 0.64-2.39]) did not differ substantially from conventional myocarditis (eTables 7 and 8 in Supplement 1).
Medical Procedures and Drugs by Myocarditis Type
The evolution of the medical procedures and drugs administered according to myocarditis group in the 18 months following hospital discharge is presented in the Figure, with additional outcomes presented in eTable 9 in Supplement 1. After standardization, the frequency of medical procedures (cardiac imaging, troponin assay, stress test) and drug prescriptions followed a similar trend for patients with postvaccine or conventional myocarditis.
Figure. Medical Procedures and Treatments Over 18 Months of Follow-Up.
Postvaccine and post–COVID-19 myocarditis shown vs conventional myocarditis. Comparisons were standardized according to sociodemographic characteristics and comorbidities of conventional myocarditis (target group through a weighted generalized estimating equation model).
aβ-blockers and/or drugs acting on the renin angiotensin system.
bCoronary angiography and/or computed tomographic scan.
Discussion
This nationwide population-based study is the first to describe the evolution of postvaccine myocarditis with an 18-month follow-up after hospitalization. Unlike patients with post–COVID-19 myocarditis, those with postvaccine myocarditis had fewer hospital readmissions for myopericarditis, other cardiovascular events, or all-cause death as a composite outcome than those with conventional myocarditis. The differences in clinical outcomes observed between the groups cannot be interpreted as causal effects, because the type of myocarditis is not modifiable.
Several studies have reported reassuring results for the prognosis of patients with postvaccine myocarditis at discharge, with a low likelihood of cardiac dysfunction at presentation and generally rapid recovery. However, residual symptoms20,21 and diagnostic abnormalities, such as altered myocardial deformation or the persistence of late gadolinium enhancement,9,20,22,23,24,25,26 were observed on cardiac magnetic resonance imaging after up to 1 year of follow-up. Although the presence of late gadolinium enhancement is an indicator of cardiac injury and fibrosis and is associated with a worse form for patients with classic acute myocarditis,24,27 its persistence over time and its prognostic value are less well established.
The current results are consistent with those of Husby et al.12 Their study outcome was limited to heart failure occurring during the first 3 months after discharge.25 The current study was able to extend the analysis to other cardiovascular complications and to benefit from a much longer follow-up period and standardization for multiple patient characteristics.
Part of the lower incidence of all-cause hospitalization observed in postvaccine myocarditis compared with conventional myocarditis might be explained by the more varied etiology of conventional myocarditis cases. For example, cases linked to inflammatory disease may require more hospital follow-up due to the underlying pathology and have more frequent cardiovascular comorbidities and risk factors. In the current study, no patient with postvaccine myocarditis received a heart transplant and 2 (0.4%) required extracorporeal membrane oxygenation, which is consistent with other studies.28,29,30
The American Heart Association and the American College of Cardiology guidelines advise that patients with myocarditis be instructed to refrain from competitive sports for 3 to 6 months and to have their health condition assessed prior to the resumption of sports.8,10 Myocarditis in athletes is receiving increasing attention, mainly because of the particular risk of sudden cardiac death it presents.31 In the current study, 1 patient with postvaccine myocarditis died during the follow-up after receiving extracorporeal membrane oxygenation, with myocarditis being the most likely cause of death. Although rare, this unfavorable outcome has already been reported in the literature.32,33
The mechanisms producing myocardial injury after administration of a COVID-19 mRNA vaccine are not well understood,34 with various hypotheses such as an altered gene expression, direct immune activation by mRNA, molecular mimicry, immune dysregulation, or aberrant cytokine expression. The current analyses might suggest a difference in the strength of the association with clinical outcomes by type of mRNA vaccine. Considering the small number per subgroup, with relatively rare events, further specific studies on this subject are required.
Although the main strength of this study lies in the large sample size, its population-based nature and the assessment of cases and vaccine exposure in comprehensive, high-quality databases, this study has other strengths. First, the data enabled the longest follow-up to date, with most patients having had time to recover without developing complications, although medical follow-up still appears necessary for some and a small proportion experienced a cardiovascular event. Second, although misclassification of cases as myocarditis might occur, which would result in an over- or underestimation of the severity of prognosis, analysis of the drugs dispensed was reassuring concerning the specificity of the cases.35 In addition, several reports36,37 have shown good International Classification of Diseases and Related Health Problems, 10th Revision coding accuracy for other cardiovascular diseases in the database used in this study whose diagnosis could be confused with that of myocarditis.
Limitations
This study also has several limitations. First, it focused on cases of myocarditis requiring hospitalization. Patients who did not seek medical attention for an acute illness, such as simple chest pain, were not included. Due to the particular attention paid to this adverse event since the COVID-19 pandemic, an overdiagnosis bias is also possible, particularly when suspecting postvaccine or post–COVID-19 myocarditis, leading to the hospitalization of patients with less severe cases. Second, the potential misclassification of myocarditis may have occurred. Vaccine-induced myocarditis was defined as hospitalization for myocarditis within 7 days of vaccination with an mRNA vaccine. In a previous study by Le Vu et al,3 associations between the risk of myocarditis and vaccination were found, reaching a 30-fold–higher risk for the second dose of the mRNA-1273 vaccine and an 8-fold–higher risk for the second dose of the BNT162b2 vaccine. Furthermore, although some studies defined postvaccine myocarditis as hospitalization for myocarditis within 21 days of vaccination with an mRNA vaccine, the study found no association between vaccination with either the BNT162b2 or mRNA-1273 vaccine and a risk of myocarditis in the 8 to 21 days after vaccination.3 When repeating the main analysis with a less restrictive definition of postvaccine myocarditis (ie, mRNA vaccine within the previous 30 days), a higher wHR was observed for postvaccine myocarditis, which suggests a less specific definition of this group. Third, the effect of the COVID-19 pandemic may have had an impact on the constitution of the conventional myocarditis group. However, similar results were obtained whether the target group was conventional myocarditis or historical myocarditis. Fourth, standardization was performed on the characteristics observed in the conventional myocarditis group, but the groups may still differ according to unmeasured characteristics. Fifth, although information on the frequency of medical procedures performed over time was available, the results of these examinations in the databases were not available, which would have provided more information on the evolution of the clinical severity of the myocarditis.
Conclusions
Patients with post–COVID-19 mRNA vaccination myocarditis, contrary to patients with post–COVID-19 myocarditis, have a lower frequency of cardiovascular complications than those with conventional myocarditis at 18 months. However, affected patients, mainly healthy young men, may require medical disease management for up to several months after hospital discharge. These elements should all be taken into account for ongoing and future mRNA vaccine recommendations.
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References
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