A randomised, open-label trial of nebulised unfractionated heparin in patients mechanically ventilated for COVID-19.

Abstract

Nebulised unfractionated heparin (UFH) might reduce time to ventilator separation in patients with COVID-19 by reducing virus infectivity, pulmonary coagulopathy, and inflammation, but clinical trial data are limited. Between 1 July 2020 and 23 March 2022, we conducted, at two hospitals in Victoria, Australia, a randomised, parallel-group, open-label, controlled trial of nebulised UFH. Eligible patients were aged 18 years or more, intubated, under intensive care unit management, had a P_aO₂ to F_IO₂ ratio of 300 or less, had acute opacities affecting at least one lung quadrant and attributed to COVID-19, and were polymerase chain reaction-positive for SARS-CoV-2 or had further testing planned. The target sample size was 270, however, the trial was stopped due to slow recruitment. There were 50 enrolments, all of whom were analysed. The median age was 55 (interquartile range (IQR) 46-64) years, 28 (56%) were males, and 46 (92%) had acute respiratory distress syndrome. Twenty-seven (54%) were randomised to nebulised heparin and 23 (46%) to standard care. Nebulised UFH was administered to the heparin group on 6 (IQR 4-10) days; median daily dose of 83 (IQR 75-88) kIU. The primary outcome, time to separation from invasive ventilation to day 28 adjusted for the competing risk of death, was not significantly different between groups but took numerically longer in the nebulised heparin group (12.0, standard deviation (SD) 10.4 days versus 7.4, SD 6.9 days; hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.31 to 1.01, P = 0.052). One patient died by day 28 in each group, fewer than expected. Time to separation from invasive ventilation among survivors to day 28 occurred more quickly than expected in the standard care group and was, without correction for multiple comparisons, significantly slower in the heparin group (11.3, SD 10.0 days, n = 26 versus 6.4, SD 5.2 days, n = 22; HR 0.52, 95% CI 0.30 to 0.92, P = 0.024). Nebulised heparin did not reduce time to ventilator separation in intubated adult patients with COVID-19. The study is limited by the small sample size and potential for sampling bias. Further study is required.