Published benefits of ivermectin use in Itajaí, Brazil for COVID-19 infection, hospitalisation, and mortality are entirely explained by statistical artefacts

Background Two recent publications by Kerr et al. (Cureus 14(1):e21272; Cureus 14(8): e28624) reported dramatic effects of prophylactic ivermectin use for both prevention of COVID-19 and reduction of COVID-19-related hospitalisation and mortality, including a dose-dependent effect of ivermectin prophylaxis. These papers have gained an unusually large public influence: they were incorporated into debates around COVID-19 policies and may have contributed to decreased trust in vaccine efficacy and public health authorities more broadly. Both studies were based on retrospective observational analysis of city-wide registry data from the city of Itajaí, Brazil from July-December 2020. Methods Starting with initially identified sources of error, we conducted a revised statistical analysis of available data, including data made available with the original papers and public data from the Brazil Ministry of Health. We identified additional uncorrected sources of bias and errors from the original analysis, including incorrect subject exclusion and missing subjects, an enrolment time bias, and multiple sources of immortal time bias. In models assuming no actual effect from ivermectin use, we conducted Monte Carlo simulations to estimate the contribution of these biases to any observed effect. Results Untreated statistical artefacts and methodological errors alone lead to dramatic apparent risk reduction associated with Ivermectin use in both studies. The magnitude of apparent risk reduction from these artefacts is comparable to the results reported by the studies themselves, including apparent protection from infection, hospitalisation, and death, and including the reported apparent dose-response relationship. Conclusions The inference of ivermectin efficacy reported in both papers is unsupported, as the observed effects are entirely explained by untreated statistical artefacts and methodological errors. Our re-analysis calls for caution in interpreting highly publicised observational studies and highlights the importance of common sources of bias in clinical research. ### Competing Interest Statement GTK receives revenue from YouTube for content on scientific misinformation and received conference travel support from the Institute for Clinical Research (Malaysia) for a talk given at the 15th National Conference for Clinical Research (NCCR). ACPA and RM declare no competing interests.} ### Funding Statement No funding was received for this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of the National University of Singapore waived ethical approval of this work based on sole use of previously approved and publicly available subject data. Reference NUS-IRB-2023-474. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data in the present work are available online at the URLs below.