Abstract: Critical Care Medicine ABSTRACT Background: Mortality in critically ill COVID-19 patients remains high. Although randomized controlled trials must continue to definitively evaluate treatments, further hypothesis-generating efforts to identify candidate treatments are required. This study’s hypothesis was that certain treatments are associated with lower COVID-19 mortality. Methods: This was a 1-yr retrospective cohort study involving all COVID-19 patients admitted to intensive care units in six hospitals affiliated with Yale New Haven Health System from February 13, 2020, to March 4, 2021. The exposures were any COVID-19–related pharmacologic and organ support treatments. The outcome was in-hospital mortality. Results: This study analyzed 2,070 patients after excluding 23 patients who died within 24 h after intensive care unit admission and 3 patients who remained hospitalized on the last day of data censoring. The in-hospital mortality was 29% (593 of 2,070). Of 23 treatments analyzed, apixaban (hazard ratio, 0.42; 95% CI, 0.363 to 0.48; corrected CI, 0.336 to 0.52) and aspirin (hazard ratio, 0.72; 95% CI, 0.60 to 0.87; corrected CI, 0.54 to 0.96) were associated with lower mortality based on the multivariable analysis with multiple testing correction. Propensity score–matching analysis showed an association between apixaban treatment and lower mortality (with vs. without apixaban, 27% [96 of 360] vs. 37% [133 of 360]; hazard ratio, 0.48; 95% CI, 0.337 to 0.69) and an association between aspirin treatment and lower mortality (with vs. without aspirin, 26% [121 of 473] vs. 30% [140 of 473]; hazard ratio, 0.57; 95% CI, 0.41 to 0.78). Enoxaparin showed similar associations based on the multivariable analysis (hazard ratio, 0.82; 95% CI, 0.69 to 0.97; corrected CI, 0.61 to 1.05) and propensity score–matching analysis (with vs. without enoxaparin, 25% [87 of 347] vs. 34% [117 of 347]; hazard ratio, 0.53; 95% CI, 0.367 to 0.77). Xu Zhao, M.D., Chan Gao, M.D., Ph.D., Feng Dai, Ph.D., Miriam M. Treggiari, M.D., Ph.D., M.P.H., Ranjit Deshpande, M.D., F.C.C.M., Lingzhong Meng, M.D. Anesthesiology 2021; 135:1076–90 EDITOR’S PERSPECTIVE What We Already Know about This Topic • While the treatment of critically ill COVID-19 patients has improved, mortality rates remain high What This Article Tells Us That Is New • In a retrospective cohort consisting of 2,070 critically ill COVID-19 patients treated in six hospitals, multivariable regression analysis showed lower in-hospital mortality associated with apixaban, aspirin, or enoxaparin treatment • Propensity score–matching analyses demonstrated lower mortality for patients receiving apixaban (27% [96 of 360] vs. 37% [133 of 360]), aspirin (26% [121 of 473] vs. 30% [140 of 473]), or enoxaparin (25% [87 of 347) vs. 34% [117 of 347]) compared to matched controls A Particular challenge of COVID-19 treatment is the high mortality, especially among critically ill patients. Although the mortality rate was estimated to be ~50% among critically ill COVID-19 patients in the early stage of the pandemic,1 a study performed at a later stage of the pandemic showed a downward trend of mortality rates from ~44% to ~19%.2 Effective treatments might be one factor responsible for this decline. Continuous efforts in Conclusions: Consistent with the known hypercoagulability in severe COVID-19, the use of apixaban, enoxaparin, or aspirin was independently associated with lower mortality in critically ill COVID-19..