ABSTRACT
Background : Hospitalized patients with COVID-19 are at increased risk for thrombosis, acute respiratory distress syndrome and death. The optimal dosage of thromboprophylaxis is unknown. Objective: To evaluate the efficacy and safety of tinzaparin in prophylactic, intermediate, and therapeutic doses in non-critical patients admitted for COVID-19 pneumonia. Design, setting, and participants : Randomized controlled, multicenter trial (PROTHROMCOVID) enrolling non-critical, hospitalized adult patients with COVID-19 pneumonia. Interventions: Patients were randomized to prophylactic (4500 IU), intermediate (100 IU/kg), or therapeutic (175 IU/kg) doses of tinzaparin during hospitalization, followed by 7 days of prophylactic tinzaparin at discharge. Measurements: The primary efficacy outcome was a composite endpoint of symptomatic systemic thrombotic events, need for invasive or non-invasive mechanical ventilation, or death within 30 days. The main safety outcome was major bleeding at 30 days. Results : Of the 311 subjects randomized, 300 were included in the analysis (mean [SD] age, 56.7 [14.6] years; males, 182 [60.7%]. The composite endpoint at 30 days from randomization occurred in 58 patients (19.3%) of the total population; 19 (17.1 %) in the prophylactic group, 20 (22.1%) in the intermediate group, and 19 (18.5%) in the therapeutic dose group (P= 0.72). No major bleeding event was reported; non-major bleeding was observed in 3.7% of patients, with no intergroup differences. Conclusions: In non-critically ill COVID-19 patients, intermediate or full-dose tinzaparin compared to standard prophylactic doses did not appear to increase benefit regarding the likelihood of thrombotic event, non-invasive ventilation or high-flow oxygen, or death. Trial Registration ClinicalTrials.gov Identifier (NCT04730856). Funding: This independent research initiative was supported by Leo-Pharma; Tinzaparin was provided by Leo Pharma.
Subject(s)
Hemorrhage , Respiratory Distress Syndrome , Pneumonia , Thrombosis , Death , COVID-19ABSTRACT
Background: Almost two years since the onset of the COVID-19 pandemic no predictive algorithm has been generally adopted, nor new tests identified to improve the prediction and management of SARS-CoV-2 infection. Methods: Retrospective observational analysis of the predictive performance of clinical parameters and laboratory tests in hospitalised patients with COVID-19. Outcomes were 28-day survival and maximal severity in a cohort of 1,579 patients and two validation cohorts of 598 and 434 patients. A pilot study conducted in a patient subgroup measured 17 cytokines and 27 lymphocyte phenotypes to explore additional predictive laboratory tests. Findings: 1) Despite a strong association of 22 clinical and laboratory variables with the outcomes, their joint prediction power was limited due to redundancy. 2) Eight variables: age, comorbidity index, oxygen saturation to fraction of inspired oxygen ratio, neutrophil-lymphocyte ratio, C-reactive protein, aspartate aminotransferase/alanine aminotransferase ratio, fibrinogen, and glomerular filtration rate captured most of the statistical predictive power. 3) The interpretation of clinical and laboratory variables was improved by grouping them in categories. 4) Age and organ damage-related tests were the best predictors of survival, and inflammatory-related tests were the best predictors of severity. 5) The pilot study identified several immunological tests (including chemokine ligand 10, chemokine ligand 2, and interleukin 1 receptor antagonist), that performed better than currently used tests. Conclusions: Currently used tests for clinical management of COVID 19 patients are of limited value due to redundancy, as all measure aspects of two major processes: inflammation, and organ damage. There are no independent predictors based on the quality of the nascent adaptive immune response. Understanding the limitations of current tests would improve their interpretation and simplify clinical management protocols. A systematic search for better biomarkers is urgent and feasible.
Subject(s)
COVID-19 , InflammationABSTRACT
Background: Modulation of the immune system to prevent lung injury is being widely used against the new coronavirus disease (COVID19) despite the scarcity of evidence. Methods: We report preliminary results from the Vall dHebron prospective cohort study at Vall dHebron University Hospital, in Barcelona (Spain), including all consecutive patients who had a confirmed infection with the severe acute respiratory syndrome coronavirus2 (SARSCoV2) and who were treated with tocilizumab until March 25th. The primary endpoint was mortality at 7 days after tocilizumab administration. Secondary endpoints were admission to the intensive care unit, development of ARDS and respiratory insufficiency among others. Results: 82 patients with COVID19 received at least one dose of tocilizumab. The mean (SD) age was 59.1 (19.8) years, 63% were male, 22% were of non Spanish ancestry, and the median (IQR) ageadjusted Charlson index at baseline was 3 (1 to 4) points. Respiratory failure and ARDS developed in 62 (75.6%) and 45 (54.9%) patients, respectively. Median time from symptom onset to ARDS development was 8 (5 to 11) days. The median time from symptom onset to the first dose of tocilizumab was 9 (7 to 11) days. Mortality at 7 days was 26.8%. Hazard ratio for mortality was 3.3; 95% CI, 1.3 to 8.5 (age adjusted hazard ratio for mortality 2.1; 95% CI, 0.8 to 5.8) if tocilizumab was administered after the onset of ARDS. Conclusion: Time from lung injury onset to tocilizumab administration may be critical to patient recovery. Our preliminary data could inform bedside decisions until more data from clinical trials becomes available.