A Critical Analysis of All-Cause Deaths during COVID-19 Vaccination in an Italian Province.

Immortal time bias (ITB) is common in cohort studies and distorts the association estimates between the treated and untreated. We used data from an Italian study on COVID-19 vaccine effectiveness, with a large cohort, long follow-up, and adjustment for confounding factors, affected by ITB, with the aim to verify the real impact of the vaccination campaign by comparing the risk of all-cause death between the vaccinated population and the unvaccinated population. We aligned all subjects on a single index date and considered the "all-cause deaths" outcome to compare the survival distributions of the unvaccinated group versus various vaccination statuses. The all-cause-death hazard ratios in univariate analysis for vaccinated people with 1, 2, and 3/4 doses versus unvaccinated people were 0.88, 1.23, and 1.21, respectively. The multivariate values were 2.40, 1.98, and 0.99. Possible explanations of this trend of the hazard ratios as vaccinations increase could be a harvesting effect; a calendar-time bias, accounting for seasonality and pandemic waves; a case-counting window bias; a healthy-vaccinee bias; or some combination of these factors. With 2 and even with 3/4 doses, the calculated Restricted Mean Survival Time and Restricted Mean Time Lost have shown a small but significant downside for the vaccinated populations.

COVID-19 vaccination and all-cause and non-COVID-19 mortality. A revaluation of a study carried out in an Italian Province.

The COVID-19 vaccination prevents COVID-19 specific mortality. Well planned population-based studies, however, are necessary to evaluate the overall effectiveness of vaccination programmes. A study carried out in the province of Pescara is used to illustrate the potential biases that may affect such studies. The Pescara study analysed total and non-COVID-19 mortality and the occurrence of Potentially Vaccine-Related Serious Adverse Events (PVR-SAEs) in vaccinated and unvaccinated people, from January 2021, when vaccines became available, to July 2022. The study reported a lower probability of both total and non-COVID-19 death in vaccinated people. However, the authors did not include in the denominator of the unvaccinated cohort the population experience of the vaccinated cohort before vaccination (immortal time bias). Correcting the denominator of the unvaccinated cohort, the crude death rate of vaccinated and unvaccinated persons becomes the same. For the same reason, the unvaccinated non-COVID-19 mortality was overestimated, as was the mortality of people receiving only one or two vaccine doses. Confounding by indication and the healthy vaccinee bias will also be discussed, as well as the bias deriving by not considering the evolution of risk over time.