Analysis After PS Matching
After 1:1 PS matching, 88 patients in SoC and 88 patients in Anakinra group were matched and included into the analysis. Baseline clinical and laboratory features of the patients were described in table 1. After adjustment of potential confounders age, gender, presence of comorbidities (DM, HT, CHD, CRF, chronic lung disease, and malignancy), disease severity, vaccination history, mcHIS scores were not different between two groups (table 1). Only baseline d-dimer and peak levels of LDH were higher in Anakinra arm compared to SoC (p=0.05 and p<0.001). Severe infection (28.4% vs 16%, p=0.05; OR:3.9), development of any thromboembolic event (15.9% vs 3.4%, p=0.005; OR:7.9), PTE (12.5% vs 3.4%, p=0.026; OR:5), MI (6.8% vs 0, p=0.013; OR:6.2) were higher in SoC arm compared to Anakinra. ICU requirement and mortality did not differ between two arms (p=0.2 and p=0.4, respectively).
Patients experienced any thromboembolic event had more frequent CHD (p=0.04; OR:4.1), critical illness (p<0.001; OR:12.5), lower hemoglobin and baseline ferritin levels (p=0.03 and p=0.04, respectively), higher mcHIS scores (p=0.001), higher peak levels of CRP (p<0.001), d-dimer (p<0.001), LDH (p=0.038). Furthermore, severe infection (41% vs 20.3%, p=0.05; OR:3.9) and mortality (64.7% vs 27.7%, p=0.002; OR:9.8) were higher in patients had any thromboembolic event than those had not (table 2). Similarly PTE was higher in patients had critical illness (p=0.002; OR:9.5), lower hemoglobin and ferritin levels (p=0.02 and p=0.04, respectively), higher mcHIS score (p=0.002), peak levels of CRP (p<0.001), d-dimer (p<0.001), pneumothorax (p=0.03; OR:4.8), MI (p<0.001; OR:15), and mortality (p=0.03; OR:4.7) (table 3). PTE development was associated with peak levels of d-dimer levels (p=0.02, OR:1.08, 95% CI: 1.01-1.15) in multivariate analysis.
Development of MI was higher in patients had history of CHD and malignancy (p=0.007; OR:7.3 and p=0.02; OR:5.5, respectively), critical illness (p=0.02; OR:5.4), higher mcHIS scores (p=0.02), peak levels of CRP (p=0.043), d-dimer (p=0.03), LDH (p=0.004) (table 4). MI was also higher in SoC (P=0.016; OR:6.2) and patients had mortality (p<0.001; OR:13.7) in univariate analysis. MI development was associated with the history of CHD (p=0.038, OR:6.9, 95% CI:1.1-42.3) and PTE (p=0.008, OR:11.5, 95% CI:1.9-69.5) in multivariate analysis.
In survival analysis, development of any thromboembolic event, PTE, and MI were higher in SoC compared to Anakinra (Log-Rank; p=0.003 [figure 1], p=0.003 [supplementary figure 4], and p=0.007 [supplementary figure 5], respectively). Survival rate was also lower in patients with SoC arm than Anakinra in patients who had any thromboembolic event as well as MI (Log-Rank; p=0.03 [figure 2] and p<0.001 [figure 3], respectively). Survival rate of patients with and without PTE did not differ in patients with COVID-19 (supplementary figure 6).
ROC analysis revealed a cut-off value of d-dimer for the development of any thromboembolic event 16.75 (Area under curve [AUC]: 0.804, p<0.001 [95% CI: 0.710-0.898]) with 61.9% sensitivity and 84.8% specificity (likelihood ratio [LR]:4), for the development of PTE 14.97 (AUC: 0.867, p<0.001 [95% CI: 0.774-0.960]) with 86.7% sensitivity and 83.5% specificity (LR:5.3), for the development of MI 5.83 (AUC: 0.736, p<0.016 [95% CI: 0.585-0.887]) with 66.7% sensitivity and 66.7% specificity (LR:2) (Supplementary figure 7,8, and 9, respectively). Cut-off value of mcHIS score for the development of any thromboembolic event 3.5 (AUC: 0.726, p=0.001 [95% CI: 0.632-0.821]) with 71.4% sensitivity and 63.2% specificity (LR:1.94), for the development of PTE 3.5 (AUC: 0.740, p=0.002 [95% CI: 0.624-0.855]) with 73.3% sensitivity and 62.4% specificity (LR:1.95), for the development of MI 3.5 (AUC: 0.750, p=0.01 [95% CI: 0.630-0.870]) with 77.8% sensitivity and 61.7% specificity (LR:2) (Supplementary figure 10,11, and 12, respectively). Cut-off value of peak levels of CRP for the development of any thromboembolic event 171.2 mg/L (AUC: 0.780, p<0.001 [95% CI: 0.684-0.875]) with 76.5% sensitivity and 72.3% specificity (LR:2.8), for the development of PTE 201 mg/L (AUC: 0.800, p<0.001 [95% CI: 0.694-0.905]) with 71.4% sensitivity and 78.4% specificity (LR:3.3), for the development of MI 145.3 mg/L (AUC: 0.743, p=0.043 [95% CI: 0.629-0.857]) with 100% sensitivity and 54.7% specificity (LR:2.2) (Supplementary figure 13,14, and 15, respectively). Other results of ROC analysis were shown in table 5 and supplementary figure 16 and 17).