Investigational medications in 9,638 hospitalized patients with severe COVID-19: lessons from the “fail-and-learn” strategy during the first two waves of the pandemic in 2020

Background: The early surge of the novel coronavirus disease 2019 (COVID-19) pandemic introduced a signi cant clinical challenge due to the high case-fatality rate in absence of evidence-based treatment recommendations. The empirical modalities were relegated to historical expertise from the traditional management of acute respiratory distress syndrome (ARDS) in conjunction with off-label pharmaceutical agents endorsed under the "emergency use authorization" paradigm by regulatory agencies. This study was designed to evaluate the insights from the "fail-and-learn" strategy in 2020 before the availability of COVID-19 vaccines and access to reliable insights from high-quality randomized controlled trials. Methods: A retrospective, multicenter, propensity-matched, case-control study was performed on a data registry comprising 186 hospitals from a national health care system in the United States, designed to investigate the e cacy of empirical treatment modalities during the early surge of the COVID-19 pandemic in 2020. Re ective of the time-windows of the initial two surges of the pandemic in 2020, patients were strati ed into "early" (March 1-June 30) versus "late" (July 1-December 31) study cohorts. Logistic regression was applied to determine the e cacy of prevalent medications (remdesivir, azithromycin, hydroxychloroquine, corticosteroids, tocilizumab) and supplemental oxygen delivery modalities (invasive vs. non-invasive ventilation) on patient outcomes. The primary outcome measure was in-hospital mortality. Group comparisons were adjusted for covariates related to age, gender, ethnicity, body weight, comorbidities, and treatment modalities pertinent to organ failure replacement. Results: From a total of 87,788 patients in the multicenter data registry screened in this study, 9,638 patients were included who received 19,763 COVID-19 medications during the rst two waves of the 2020 pandemic.The results showed inconclusive variable results pertinent to the impact of empirical medications on patient outcomes. In contrast, the necessity for oxygen supply showed signi cantly increased odds of mortality beyond the effect of the investigational medications. Of all the covariates associated with increased mortality, invasive mechanical ventilation had the highest odds ratios of 8.34 in the rst surge and 9.46 in in the second surge of the pandemic (P<0.01). Conclusion: This retrospective multicenter observational cohort study on 9,638 hospitalized patients with severe COVID-19 during revealed that the necessity for invasive ventilation had the highest odds of mortality, beyond the variable effects observed by administration of the prevalent EUA-approved investigational drugs during the rst two surges of the early 2020 pandemic in the United States.