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.

Disclosures

Anesthesiology. 2021;135(6):1076-1090. 

In This Article

Results

Study Population

From February 13, 2020, to March 4, 2021 (1 yr and 3 weeks), a total of 2,096 patients were treated for COVID-19–related complications in Yale New Haven Health System's ICUs (Figure 1). We excluded 23 patients who died within 24 h after ICU admission and 3 patients who remained hospitalized on the last day of data censoring. The final analysis involved 2,070 patients, including 856 (41%) patients admitted to ICU during the first phase, 138 (6.7%) patients during the second phase, 400 (19.3%) patients during the third phase, and 676 (32.7%) patients during the fourth phase (Figure S1 in Supplemental Digital Content, http://links.lww.com/ALN/C693). The study population had a mean age of 65 yr (SD, 16 yr; N = 2,070) and a male patient percentage of 58.8% (1,218 of 2,070; Table 1 and table S1 in Supplemental Digital Content, http://links.lww.com/ALN/C693).

Figure 1.

Patients and analyses. ICU, intensive care unit.

Descriptive Data

The potential COVID-19–related treatments are presented in table S2 in Supplemental Digital Content (http://links.lww.com/ALN/C693), with most treatments given to less than 5% of the study population. The treatments included in the multivariable analysis are presented in Table 2. The potential confounders included in the multivariable analysis are presented in table S3 in Supplemental Digital Content (http://links.lww.com/ALN/C693).

Outcome Data

A total of 593 patients died during hospitalization, and 1,477 patients were discharged from the hospital alive. The all-cause in-hospital mortality was 28.6% (593 of 2,070). The mortality was 31.8% (272 of 856) during the first pandemic phase, 10.1% (14 of 138) during the second pandemic phase, 26.8% (107 of 400) during the third pandemic phase, and 29.6% (200 of 676) during the fourth pandemic phase. The median hospital stay was 16 days (interquartile range, 10 to 27), and the median ICU stay was 6 days (interquartile range, 2 to 13).

Treatments Associated With Lower Mortality

The following treatments were associated with lower mortality based on the multivariable analysis: atazanavir (hazard ratio, 0.58; 95% CI, 0.393 to 0.89; P = 0.006), enoxaparin (hazard ratio, 0.82; 95% CI, 0.69 to 0.97; P = 0.021), heparin (hazard ratio, 0.79; 95% CI, 0.66 to 0.95; P = 0.011), apixaban (hazard ratio, 0.42; 95% CI, 0.363 to 0.48; P < 0.001), aspirin (hazard ratio, 0.72; 95% CI, 0.60 to 0.87; P < 0.001), famotidine (hazard ratio, 0.364; 95% CI, 0.174 to 0.76; P = 0.008), and conventional oxygen therapy (hazard ratio, 0.51; 95% CI, 0.327 to 0.81; P = 0.004; Table 2). The results of the 23 hypotheses, corresponding to all treatments included in the multivariable analysis, were corrected using the Bonferroni method. After multiple testing correction, only apixaban (corrected CI, 0.336 to 0.52; corrected P < 0.001) and aspirin (corrected CI, 0.54 to 0.96; corrected P = 0.010) remained significantly associated with lower mortality. The results of the univariate analyses are presented in table S4 in Supplemental Digital Content (http://links.lww.com/ALN/C693).

Propensity Score–Matching Analysis for Apixaban

The association between apixaban and mortality was further evaluated using propensity score–matching analysis as this association remained significant after the multivariable analysis with multiple testing correction. The propensity score matching generated two well balanced cohorts: one comprising 360 patients who received apixaban treatment and the other comprising 360 patients who never received apixaban treatment (Table 3 and table S5 in Supplemental Digital Content, http://links.lww.com/ALN/C693). The mortality was 26.7% (96 of 360) in patients treated with apixaban and 36.9% (133 of 360) in patients not treated with apixaban. Apixaban treatment had a significant association with lower mortality (hazard ratio, 0.48; 95% CI, 0.337 to 0.69; P < 0.001), reflecting a 52% lower mortality risk in apixaban-treated patients compared to patients never treated with apixaban. The respective survival probabilities of patients who received and did not receive apixaban treatment are presented in Figure 2A. An additional stratified multivariable Cox regression analysis based on the matched cohorts also showed a significant association between apixaban treatment and lower mortality (hazard ratio, 0.388; 95% CI, 0.254 to 0.59; P < 0.001), with the covariates including enoxaparin, aspirin, and dexamethasone.

Figure 2.

Survival probability for patients treated and not treated with apixaban (A), enoxaparin (B), and aspirin (C). The patients are matched using propensity score matching. ICU, intensive care unit.

Propensity Score–Matching Analysis for Enoxaparin

Enoxaparin was the anticoagulant of choice for hospitalized COVID-19 patients during this pandemic. In total, 72.7% of our patients received enoxaparin, whereas only 19.7% received apixaban. The multivariable analysis suggested an association between enoxaparin treatment and lower mortality, although this association was no longer significant after multiple testing correction (Table 2). This result might be due to overcorrection. To further explore this association, we used propensity score–matching analysis to estimate the association between enoxaparin and mortality.

The propensity score matching generated two well balanced cohorts: one comprising 347 patients who received enoxaparin treatment and the other comprising 347 patients who never received enoxaparin treatment (Table 4 and table S6 in Supplemental Digital Content, http://links.lww.com/ALN/C693). The mortality was 25.1% (87 of 347) in patients treated with enoxaparin and 33.7% (117 of 347) in patients never treated with enoxaparin. Enoxaparin treatment had a significant association with lower mortality (hazard ratio, 0.53; 95% CI, 0.367 to 0.77; P < 0.001), reflecting a 47% lower mortality risk in enoxaparin-treated patients compared to patients never treated with enoxaparin. The respective survival probabilities of patients who received and did not receive enoxaparin are presented in Figure 2B. An additional stratified multivariable Cox regression analysis based on the matched cohorts also showed a significant association between enoxaparin treatment and lower mortality (hazard ratio, 0.55; 95% CI, 0.373 to 0.81; P = 0.002), with the covariates including apixaban, aspirin, and dexamethasone.

Propensity Score–Matching Analysis for Aspirin

The association between aspirin and mortality was further evaluated using propensity score–matching analysis because this association remained significant after the multivariable analysis with multiple testing correction. The propensity score matching generated two well balanced cohorts: one comprising 473 patients who received aspirin treatment and the other comprising 473 patients who never received aspirin treatment (Table 5 and table S7 in Supplemental Digital Content, http://links.lww.com/ALN/C693). The mortality was 25.6% (121 of 473) in patients treated with aspirin and 29.6% (140 of 473) in patients not treated with aspirin. Aspirin treatment had a significant association with lower mortality (hazard ratio, 0.57; 95% CI, 0.41 to 0.78; P < 0.001), reflecting a 43% lower mortality risk in aspirin-treated patients compared to patients never treated with aspirin. The respective survival probabilities of patients who received and did not receive aspirin treatment are presented in Figure 2C. An additional stratified multivariable Cox regression analysis based on the matched cohorts also showed a significant association between aspirin treatment and lower mortality (hazard ratio, 0.61; 95% CI, 0.43 to 0.86; P = 0.005), with the covariates including apixaban, enoxaparin, and dexamethasone.

Exploratory Analysis

Association Modification by Apixaban Dose. Apixaban was administered in two different doses: a prophylactic dose (2.5 or 5 mg two times daily) in 80% (328 of 408) of patients and a therapeutic dose (10 mg two times daily) in 20% (80 of 408) of patients (table S8 in Supplemental Digital Content, http://links.lww.com/ALN/C693). The 360 matched pairs based on apixaban treatment were split into two subgroups: one subgroup had patients treated with prophylactic apixaban versus matched patients never treated with apixaban (N, 287 vs. 287), whereas the other subgroup had patients treated with therapeutic apixaban versus matched patients never treated with apixaban (N, 73 vs. 73; table S9 in Supplemental Digital Content, http://links.lww.com/ALN/C693). Prophylactic apixaban was associated with lower mortality (30.7% vs. 38.0%; hazard ratio, 0.50; 95% CI, 0.340 to 0.73; P < 0.001), whereas therapeutic apixaban was not associated with lower mortality (11.0% vs. 32.9%; hazard ratio, 0.385; 95% CI, 0.137 to 1.08; P = 0.069).

Association Modification by Enoxaparin Dose. Enoxaparin was administered in two different doses: a prophylactic dose (40 mg one time daily or 0.5 mg/kg two times daily) in 79.3% (1,192 of 1,504) of patients and a therapeutic dose (1 mg/kg two times daily) in 20.7% (312 of 1,504) of patients (table S10 in Supplemental Digital Content, http://links.lww.com/ALN/C693). The 347 matched pairs per enoxaparin treatment were split into two subgroups: one subgroup had patients treated with prophylactic enoxaparin versus matched patients never treated with enoxaparin (N, 289 vs. 289), whereas the other subgroup had patients treated with therapeutic enoxaparin versus matched patients never treated with enoxaparin (N, 58 vs. 58; table S11 in Supplemental Digital Content, http://links.lww.com/ALN/C693). Prophylactic and therapeutic enoxaparin were both associated with lower mortality (25.6% vs. 31.8%; hazard ratio, 0.65; 95% CI, 0.43 to 0.97; P = 0.036 and 22.4% vs. 43.1%; hazard ratio, 0.191; 95% CI, 0.066 to 0.55; P = 0.002, respectively).

Association Modification by Aspirin Dose. Aspirin was administered in two different doses: a low dose (81 mg one time daily) in 89.2% (1,209 of 1,355) of patients and a high dose (300/325 mg one time daily) in 10.8% (146 of 1,355) of patients (table S12 in Supplemental Digital Content, http://links.lww.com/ALN/C693). The 473 matched pairs based on aspirin treatment were split into two subgroups: one subgroup had patients treated with low-dose aspirin versus matched patients never treated with aspirin (N, 422 vs. 422), whereas the other subgroup had patients treated with high-dose aspirin versus matched patients never treated with aspirin (N, 51 vs. 51; table S13 in Supplemental Digital Content, http://links.lww.com/ALN/C693). Low-dose aspirin was associated with lower mortality (24.6% vs. 30.6%; hazard ratio, 0.53; 95% CI, 0.375 to 0.74; P < 0.001), whereas high-dose aspirin was not associated with lower mortality (33.3% vs. 21.6%; hazard ratio, 1.14; 95% CI, 0.41 to 3.15; P = 0.796).

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