Chronologic Bias, Confounding by Indication, and COVID-19 Care.

To the Editor:

The authors of “Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019” in CHEST (January 2021) deserve praise for their study, which to date is the highest quality evidence to evaluate the use of ivermectin in patients with this disease.

Propensity score matching, like other adjustment techniques, can only account for between-group differences that are included in the propensity score itself. One possible variable that the authors themselves raise in their discussion, but did not adjust for, is “timing bias” or chronologic bias. The authors state “more of the control group was enrolled in the first weeks of the study.” If care changed in other ways at the same time ivermectin became the norm in the authors’ hospital, then the outcomes could be ascribed falsely to ivermectin. Nationally available data have shown declining in-hospital mortality rates during this time period. Unlike most design flaws, chronologic bias could be tested for simply by adding date of admission to the propensity score. If this makes matching impossible, then chronologic bias becomes likely. We hope the authors consider this analysis.

Further, the unusually common administration of ivermectin to admitted patients during this timeframe consecutively, particularly later in the study, suggests that ivermectin was effectively the standard of care at these sites and implies that patients who did not receive it may have differed systematically in other, unmeasured ways. This is a form of confounding by indication, is more statistically intractable, and may have also led to misleading results during the early period of the pandemic with anticoagulation and hydroxychloroquine for hospitalized patients with COVID-19.