Effect of Heparin and Tocilizumab in Patients with Severe COVID-19: The HEPMAB Randomized Clinical Trial (preprint)

BackgroundClinical presentation of severe Coronavirus disease 2019 (COVID-19) is associated to an intense inflammatory response and thrombogenesis. The benefits of the association of interleukin-6 receptor blockade (tocilizumab) and therapeutic-dose anticoagulation remains unclear. We aimed to assess whether heparin and tocilizumab could effectively reduce inflammation and thrombogenesis in severe COVID-19 patients. MethodsThis is an open-label, multicenter, randomized, clinical trial, involving patients with severe COVID-19 infection. Eligible patients were randomly assigned in a 1:1:1:1 ratio to receive either therapeutic or prophylactic anticoagulation with heparin, with or without an intravenous single dose of tocilizumab. The participants in the study were assigned to one of the four distinct arms: 1) therapeutic anticoagulation; 2) prophylactic anticoagulation; 3) therapeutic anticoagulation plus a single intravenous dose of tocilizumab; and 4) prophylactic anticoagulation plus a single intravenous dose of tocilizumab. The primary outcome was clinical improvement at day 30, defined as a composite of hospital discharge and/or a reduction of at least 2 points of the modified ordinal scale of 7 points recommended by the World Health Organization. ResultsWe enrolled 308 patients. Patients randomized to receive therapeutic anticoagulation more frequently had clinical improvement at day 30 when compared to the prophylactic anticoagulation patients [64/75 (85%) versus 51/80 (64%), odds ratio, 3.31; 95% confidence interval, 1.51; 7.26 P=0.003]. Major bleeding was more frequent in the therapeutic anticoagulation group (6.7%) and in the therapeutic anticoagulation plus tocilizumab group (5.0%), compared to the prophylactic anticoagulation group (P=0.02). All-cause mortality at day 30 was significantly lower in therapeutic anticoagulation group (9.3%), when compared to prophylactic anticoagulation group (28.7%), therapeutic anticoagulation plus tocilizumab group (21.5%) and prophylactic anticoagulation plus tocilizumab group (25.7%), P=0.02. ConclusionsIn this randomized clinical trial involving severe COVID-19 patients, therapeutic anticoagulation resulted in clinical improvement at 30 days. Even if therapeutic anticoagulation increased bleeding, it was associated with a reduced overall mortality. Tocilizumab did not provide additional benefits to heparin in COVID-19 patients. Trial registrationClinicaltrials.gov NCT04600141. Registered October 22, 2020. https://www.clinicaltrials.gov/study/NCT04600141?term=NCT04600141&rank=1

Lung Ultrasound Score: A Potential Prediction Tool In Covid-19 (preprint)

1. Background: During the COVID-19 pandemic, adequate management of available resources may be key to overcoming the excess of seriously ill patients and saving lives. Creating tools to assess disease severity is one of the most important aspects for reducing the burden on emergency departments. Lung ultrasound has high accuracy for diagnosis of pulmonary diseases; however, there are no prospective studies demonstrating that lung ultrasound can predict outcomes in COVID-19. We hypothesized that Lung Ultrasound Score (LUSS) at hospital admission would be able to predict the outcomes of patients with COVID-19.2. Methods: Prospective cohort study conducted from 14 March through 6 May 2020 in the Emergency Department (ED) of an urban, academic, level I trauma center. This 2,200-bed hospital has been designated exclusive for COVID-19 patients for the duration of the pandemic. Patients aged 18 years and older and admitted to the ED with confirmed COVID-19 were considered eligible. Emergency physicians performed lung ultrasounds and calculated LUSS, which was tested for correlation with outcomes.3. Results: Primary endpoint was death from any cause. Secondary endpoints were ICU admission and endotracheal intubation for respiratory failure. Among 180 patients with confirmed COVID-19 who were enrolled (mean age, 60 years; 105 male), the average LUSS was 18.7 ± 6.8. LUSS correlated with findings on chest CT and was able to predict the estimated extent of parenchymal involvement (mean LUSS with < 50% involvement on chest CT, 15±6.7 vs. 21±6.0 with >50% involvement, p<0.001), death (AUC 0.71, OR 1.13, 95%CI 1.07 to 1.21; p < 0.001), endotracheal intubation (AUC 0.75, OR 1.17, 95%CI 1.09 to 1.26; p < 0.001), and ICU admission (AUC: 0.71, OR 1.14, 95%CI 1.07 to 1.21; p < 0.001). 4. Conclusion: LUSS was a good predictor of death, ICU admission, and endotracheal intubation in COVID-19 patients. 5. Trial RegistrationThis protocol was approved by the local Ethics Committee number 3.990.817 (CAAE: 30417520.0.0000.0068).