Treatments Associated With Lower Mortality Among Critically Ill COVID-19 Patients

A Retrospective Cohort Study

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(6):1076-1090. 

In This Article

Abstract and Introduction


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).

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 patients.


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 discovering effective treatments are needed and have been ongoing as evidenced by the recent trials exploring the effectiveness of therapeutic versus prophylactic anticoagulation in hospitalized and critically ill patients.[3–5] With the passing of the COVID-19 pandemic's first anniversary and the surge of the Delta variant, a look back at the data accumulated over 1 yr provides an opportunity to identify potentially effective treatments. Such an approach could corroborate established treatments or generate hypotheses for future investigations.

This retrospective cohort study hypothesized that certain treatments would be associated with lower mortality in patients treated in intensive care units (ICUs) for COVID-19–related complications. Our objective was to identify the treatments associated with lower COVID-19 mortality based on multivariable analysis. The reproducibility of the associations identified by multivariable analysis was evaluated by propensity score–matching analysis. This study was based on all COVID-19 patients treated in the ICUs in hospitals affiliated with Yale New Haven Health System headquartered in New Haven, Connecticut.