We appreciate Hunt et al.1 for reporting their observational study investigating the association between several medications of interest and risk of mortality in patients with COVID-19. One of the findings in their multivariate analysis attracted our attention, in which the use of statins in patients with COVID-19 was associated with a significantly reduced risk of death (relative risk: 0.54; 95% confidence interval [CI] 0.46–0.62). Indeed, the positive finding regarding the use of statins in patients with COVID-19 is in concordance with the findings reported in a meta-analysis of observational studies.2

Nevertheless, the findings of these observational studies1,2 are in contrast with the observations of a randomized controlled trial (INSPIRATION-S trial)3 which investigated the efficacy of atorvastatin among critically ill patients with COVID-19. The randomized trial reported no significant difference in all-cause mortality between patients randomized to atorvastatin relative to placebo (odds ratio: 0.84; 95% CI 0.58–1.22).

We are concerned that conflicting findings about statin therapy in patients with COVID-19 between real-life observational studies and the randomized clinical trial may lead to premature abandonment of the efforts to investigate the use of statins in this population of patients. One possible explanation of the discrepancy is that statins’ ability to reduce neutrophil extracellular trap (NET) formation upon the development of COVID-19 is the main driver of their mortality benefits, instead of their anti-inflammatory activities, as has been widely hypothesized.4

A growing understanding of COVID-19 has discovered that both NET formation (during the early stage) and impaired NET degradation (during the late stage) contribute to its pathophysiology.5 The findings where the use of statins was associated with mortality benefits as reported in observational studies1,2 may be due to the inhibition of NET formation by statins during the early stage of illness since patients most likely receive statins even before the diagnosis of COVID-19. De novo introduction of statins after diagnosis of severe COVID-19, as in the INSPIRATION-S trial, may be too late for the benefits of impaired NET degradation to be helpful.

Therefore, we believe future clinical trials investigating the efficacy of statins in COVID-19 should preferably administer these agents for pre-exposure prophylaxis and target especially high-risk patients prone to mortality.