Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

Background: Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care. Methods: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg–cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab–cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing. Findings: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab–cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab–cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97–1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97–1·34]; p=0·13). Mortality was lower in the tixagevimab–cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50–0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab–cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68–1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab–cilgavimab group and 38 (5%) in the placebo group. Interpretation: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower. Funding: US National Institutes of Health (NIH) and Operation Warp Speed

A population-based phenome-wide association study of cardiac and aortic structure and function

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart–brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers

The effects of advanced monitoring on hemodynamic management in critically ill patients: a pre and post questionnaire study

In critically ill patients, many decisions depend on accurate assessment of the hemodynamic status. We evaluated the accuracy of physicians' conventional hemodynamic assessment and the impact that additional advanced monitoring had on therapeutic decisions. Physicians from seven European countries filled in a questionnaire in patients in whom advanced hemodynamic monitoring using transpulmonary thermodilution (PiCCO system; Pulsion Medical Systems SE, Feldkirchen, Germany) was going to be initialized as part of routine care. The collected information included the currently proposed therapeutic intervention(s) and a prediction of the expected transpulmonary thermodilution-derived variables. After transpulmonary thermodilution measurements, physicians recorded any changes that were eventually made in the original therapeutic plan. A total of 315 questionnaires pertaining to 206 patients were completed. The mean difference (±standard deviation; 95 % limits of agreement) between estimated and measured hemodynamic variables was -1.54 (±2.16; -5.77 to 2.69) L/min for the cardiac output (CO), -74 (±235; -536 to 387) mL/m(2) for the global end-diastolic volume index (GEDVI), and -0.5 (±5.2; -10.6 to 9.7) mL/kg for the extravascular lung water index (EVLWI). The percentage error for the CO, GEDVI, and EVLWI was 66, 64, and 95 %, respectively. In 54 % of cases physicians underestimated the actual CO by more than 20 %. The information provided by the additional advanced monitoring led 33, 22, 22, and 13 % of physicians to change their decisions about fluids, inotropes, vasoconstrictors, and diuretics, respectively. The limited clinical ability of physicians to correctly assess the hemodynamic status, and the significant impact that more physiological information has on major therapeutic decisions, support the use of advanced hemodynamic monitoring in critically ill patients