A comparison of four self-controlled study designs in an analysis of COVID-19 vaccines and Myocarditis using Five European Databases

Abstract

AbstractIntroductionThe aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis.MethodsWe used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures.ResultsWe included 1,757 cases of myocarditis. In unadjusted analyses, agreement between study designs varied by vaccine brand. There was good agreement between all designs for AstraZeneca and Pfizer, but for Moderna we found harmful incidence rate ratios (IRR) using the standard and extended SCCS (standard SCCS: IRR = 3.12, 95%CI = 1.53 – 6.40; extended SCCS: IRR = 2.43, 95%CI = 1.11 – 5.33) compared with no association with the SCRIs (SCRI-pre: IRR = 0.60, 95%CI = 0.27 – 1.33; SCRI-post: IRR = 0.86, 95%CI = 0.34 – 2.19), although confidence intervals were wide. There was very good agreement between all designs for the unadjusted second dose analyses, confirming the known harmful association between the second dose of Moderna and Pfizer vaccines and myocarditis.ConclusionsIn the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures.