Validation of myocarditis diagnoses in the Swedish patient register for analyses of potential adverse reactions to COVID-19 vaccines.

Background: Coronavirus disease 2019 (COVID-19) mRNA vaccines are associated with an increased risk of myocarditis using hospital discharge diagnoses as an outcome. The validity of these register-based diagnoses is uncertain. Methods: Patient records for subjects < 40 years of age and a diagnosis of myocarditis in the Swedish National Patient Register were manually reviewed. Brighton Collaboration diagnosis criteria for myocarditis were applied based on patient history, clinical examination, laboratory data, electrocardiograms, echocardiography, magnetic resonance imaging and myocardial biopsy. Poisson regression was used to estimate incidence rate ratios, comparing the register-based outcome variable to validated outcomes. Interrater reliability was assessed by a blinded re-evaluation. Results: Overall, 95.6% (327/342) of cases registered as myocarditis were confirmed (definite, probable or possible myocarditis according to Brighton Collaboration diagnosis criteria, positive predictive value 0.96 [95% CI 0.93-0.98]). Of the 4.4% (15/342) cases reclassified as no myocarditis or as insufficient information, two cases had been exposed to the COVID-19 vaccine no more than 28 days before the myocarditis diagnosis, two cases were exposed >28 days before admission and 11 cases were unexposed to the vaccine. The reclassification had only minor impact on incidence rate ratios for myocarditis following COVID-19 vaccination. In total, 51 cases were sampled for a blinded re-evaluation. Of the 30 randomly sampled cases initially classified as either definite or probably myocarditis, none were re-classified after re-evaluation. Of the in all 15 cases initially classified as no myocarditis or insufficient information, 7 were after re-evaluation re-classified as probable or possible myocarditis. This re-classification was mostly due to substantial variability in electrocardiogram interpretation. Conclusion: This validation of register-based diagnoses of myocarditis by manual patient record review confirmed the register diagnosis in 96% of cases and had high interrater reliability. Reclassification had only a minor impact on the incidence rate ratios for myocarditis following COVID-19 vaccination.

Vaccine development during a pandemic: General lessons for clinical trial design

The COVID-19 pandemic triggered an unprecedented research effort to develop vaccines and therapeutics. Urgency dictated that development and regulatory assessment were accelerated, while maintaining all standards for quality, safety and efficacy. To speed up evaluation the European Medicines Agency (EMA) implemented "rolling reviews” allowing developers to submit data for assessment as they became available.We discuss the clinical trial designs and the applied statistical approaches in vaccine efficacy trials, focusing on aspects such as multiple testing, interim and updated analyses, and reporting of results for the first four vaccines recommended for approval by the EMA. The fast accrual of COVID-19 cases in the clinical vaccine efficacy trials led to multiple data updates within a short time frame, which had consequences for the evaluation and interpretation of results. Key trial results are discussed in the light of these aspects. Notably, the aspects discussed did not affect the benefit/risk relationship in a meaningful way, which was clearly positive for all four vaccines.Assessment of the development and evaluation of the four vaccine trials during the pandemic has led to a proposal for standardised terminology for trials with multiple analyses and a recommendation to appropriately pre-plan the timing of primary and updated analyses. For the reporting of updated estimates of vaccine efficacy, we discuss how to best describe the uncertainty around estimates of vaccine efficacy (e.g., via confidence intervals). Finally, we briefly highlight the benefit of a comprehensive discussion on estimands for vaccine efficacy trials. [ FROM AUTHOR] Copyright of Statistics in Biopharmaceutical Research is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Comparison of years of life lost to 1,565 suicides versus 10,650 COVID-19 deaths in 2020 in Sweden: four times more years of life lost per suicide than per COVID-19 death.

Background: The burden of disease from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is large; however, suicide affects the population year after year. From a public health perspective, it is important to not neglect contributors to the total burden of disease. The aim of this paper is to compare years of life lost (YLL) to suicide with those lost to coronavirus disease 2019 (COVID-19). Methods: A nationwide cohort study in 2020, in Sweden. YLL was measured as the sex- and age-specific remaining life expectancy at the time of the person's death based on the death risks that pertained to the Swedish population in 2019. YLL to suicide was compared to YLL to COVID-19 and presented by sex and age groups. Suicide deaths in 2020 were estimated as the annual average of suicides in 2015-2019. Results: Annual average of suicide was 1,565, whereof 1,076 (68.8%) men and 489 (31.2%) women. In 2020, 10,650 persons died of COVID-19, whereof 5,681 (53.3%) men and 4,969 (46.7%) women. Estimated total YLL to suicide and COVID-19 in 2020 was 53,237 and 90,116, respectively. The COVID-19 YLL to suicide YLL ratio in 2020 was 1.69 (90,116/53,237). Men accounted for 67.1% of suicide YLL and of 56.4% of COVID-19 YLL. Those 44 years or younger accounted for 60.3% of suicide YLL and 3.9% of COVID-19 YLL. Those 75 years and older accounted for 2.9% of suicide YLL and 60.9% of COVID-19 YLL. On average, each suicide generates 34 YLL (53,237/1,565), and each COVID-19 death generates 8.5 YLL (90,116/10,650). Conclusions: YLL to suicide affects Sweden year after year, foremost attributable to the younger age groups, whereas YLL to COVID-19 is foremost attributable to the elderly. On average, each suicide generates four times more YLL than a COVID-19 death. Enormous efforts and resources have been put on tackling the pandemic, and without these, the burden would probably have been much larger. However, from a public health perspective, it is important to not neglect other contributors to the total burden of disease where national efforts also may have an impact.

SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents.

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.

The profile of the COvid-19 VACcination register SAFEty study in Sweden (CoVacSafe-SE).

BACKGROUND: The coronavirus disease 2019 (COVID-19) vaccines have been rapidly implemented in national vaccination programs world-wide after accelerated approval processes. The large population exposure achieved in very short time requires systematic monitoring of safety. The Swedish Medical Products Agency has launched a project platform for epidemiological surveillance to detect and characterise suspected adverse effects of COVID-19 vaccines in Sweden. METHODS: The platform includes all individuals 12 years or older in Sweden in 2021 and will be updated annually. Data, including vaccine and COVID-19 disease data, socioeconomic and demographic data, comorbidity, prescribed medicines and healthcare utilisation outcomes, are obtained from several national registers in collaboration with other Swedish Government agencies. Data from 2015 to 2019 are used as a historical comparison cohort unexposed to both the COVID-19 pandemic and to the COVID-19 vaccines. RESULTS: The primary study cohort includes 8,305,978 adults 18 years and older permanently residing in Sweden on 31 December 2020. The historical control cohort includes 8,679,641 subjects. By 31 July 2021, around 50% of those 18 years and older and two-thirds of those 50 years and older were vaccinated with at least one dose, 90% of those 70 years or older had two doses. CONCLUSIONS: The nationwide register-based study cohort created by the Swedish Medical Products Agency with regular updates of individual level linkage of COVID-19 vaccination exposure data to other health data registers will facilitate both safety signal detection and evaluation and other pharmacoepidemiological studies.