Between February 29th and April 7th, 2020, 351 patients were admitted to the Castel San Giovanni COVID Hospital. Ninety-four patients were excluded from the analysis for the following reasons: 30 were discharged, 43 died and 17 were transferred to other care units (7 to Intensive Care Units outside our province) within 7 days. Three were not COVID–19 confirmed patients and 1 patient was undergoing hemodialysis (Fig. 1). The characteristics of the 257 patients included in the analyses are shown in Table 1.
One hundred thirty-one (51%) received prophylactic LMWH ( 60–90 I. U. /kg daily for at least 7 days) and 126 patients (49%) received therapeutic LMWH (70–100 I. U. /kg twice daily for at least 7 days) treatment.
Two hundred-thirty-two patients (90.3%) received empiric antibiotic treatment (azithromycin 500 mg/day for at least 5 days), 237 patients (92.2%) received hydroxychloroquine (200 mg twice a day for at least 5 days), 146 patients (55.7%) received corticosteroids (methylprednisolone 1 mg/Kg twice a day i.v. or dexamethasone 40 mg i.v. once a day for 3 days followed by decreasing dosage), 236 patients (91.8%) received anti-retroviral therapy (darunavir/cobicistat 800 + 150 mg, 1 tablet for 7 days and/or lopinavir/ritonavir 200 + 50 mg, 1 tablet twice a day for 7 days). Twenty-five patients (9.5%) were eligible for treatment with tocilizumab (8 mg/kg i.v. in a single or double dose). D-dimer was collected in 93 patients, and the mean peak level was 5241 µg/ml; the median level was 1489 µg/ml.
All patients required oxygen therapy: 135 patients (52,5%) needed nasal cannulas with oxygen flow ≤ 6 l/min or non-rebreather mask with oxygen flow from 10 to 15 l/min (Vent 1); 67 patients (26.1%) required non-invasive mechanical ventilation (Vent 2) and 55 patients (21.4%) required invasive mechanical ventilation (Vent 3).
Patients treated with prophylactic and therapeutic LMWH had similar demographic and clinical characteristics (Table 1). However, patients in the therapeutic LMWH group more frequently received corticosteroids, hydroxychloroquine and tocilizumab.
Hospital mortality in patients treated with therapeutic LMWH vs. prophylactic LMWH
During hospitalization, 49 patients died (49/257, 19.1%). Hospital mortality was significantly lower in patients treated with therapeutic LMWH (17/126, 13.5%) than in those treated with prophylactic LMWH (32/131, 24.4%; χ² = 4.98, p = 0.02). The crude odds ratio of mortality in patients treated with therapeutic LMWH was OR = 0.483, 95% CI 0.252–0.923, p<0.05.
When analyses were stratified by type of ventilation, patients with noninvasive mechanical ventilation (Vent–2) were those who mostly benefited from therapeutic doses of LMWH, since in these patients, the mortality was lower than in those treated with prophylactic LMWH (OR = 0.099, 95% CI 0.028–0.354, p<0.001). In patients that required the other two types of ventilation, no significant differences in mortality rate were observed (Vent1: OR = 0.853, 95% CI 0.309–2.355, p = 0.759; Vent 3: OR = 0.792, 95% CI 0.220–2.852, p = 0.721). Multivariable linear regression was conducted to determine whether therapeutic LMWH was more effective than prophylactic LMWH in reducing in-hospital mortality after controlling for concomitant administration of corticosteroids, hydroxychloroquine and tocilizumab. The results indicate a significant 62.6% reduction in the mortality risk among those treated with therapeutic LMWH (OR = 0.374, 95% CI 0.177–0.792, p = 0.01) (Table 2).
Moreover, Cox regression analysis was conducted to analyse the risk of in-hospital mortality after controlling for concomitant administration of corticosteroids, tocilizumab and hydroxycloroquine. The results indicate a significant 70.9% reduction in the mortality risk among those treated with T-LMWH (HR = 0.291, 95% CI 0.153–0.556) (Table 3 and fig. 2).
Safety of therapeutic LMWH
Two major and 1 minor bleeding episode were recorded in therapeutic LMWH patients (3/126; 2.4 %): two patients had psoas muscle hematoma that required two packed red blood cells transfusion each and one patient had gluteus muscle hematoma that recovered spontaneously. No patient needed invasive treatment.