The use of the angiotensin receptor blocker losartan in hospitalised patients with COVID-19 and acute lung injury was no better than placebo
An angiotensin receptor blocker, losartan, given to hospitalised patients with COVID-19 and acute lung injury, was no better than than placebo, according to the results of a randomised, placebo-controlled trial by researchers from the Department of Emergency Medicine, University of Minnesota, Minneapolis, US.
Drugs such as losartan affect the renin-angiotensin system (RAS), which is a complex network that has an important role in maintaining blood pressure as well as electrolyte and fluid homeostasis. Within this system, an angiotensin converting enzyme (ACE) produces angiotensin II, a potent vasoconstrictor but which also increases vascular permeability, through the release of prostaglandins to initiate an inflammatory process. Moreover, angiotensin II up-regulates the expression of soluble epoxide hydrolase (seH), higher levels of which are linked to an aggravated pulmonary inflammation and oedema and which is a key player in the pathogenesis of acute respiratory distress syndrome (ARDS). Interestingly, in the same study it was found that losartan reduced lung injury by blocking angiotensin II-induced up-regulation of seH, suggesting a potential role for the drug in patients with COVID-19. Further support for a potentially protective effect of drugs affecting the RAS came from a 2020 systematic review which concluded that the use of both angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (such as losartan), was significantly associated with lower odds of mortality compared with non-use of these drugs.
For the present trial, the US team sought to determine whether the use of losartan could reduce the acute lung injury associated with COVID-19 infection. They recruited patients hospitalised due to severe COVID-19 but who were not prescribed either an ACEi or angiotensin receptor blocker drug and randomised them, 1:1, to either losartan 50 mg twice daily or placebo and both treatments were prepared by pharmacists into a suspension and then administered for a period of 10 days. The researchers set the primary outcome as the worse recorded ratio of the arterial partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2) after 7 days, which served as a surrogate measure of respiratory failure. Secondary outcomes included an ordinal COVID-19 severity scale, the need for ventilation or vasopressors and mortality.
Losartan and COVID-19 outcomes
A total of 205 participants with a mean age of 55.2 years (60% male) were randomised to losartan (101) or placebo.
After 7 days, the mean difference in the PaO2/FiO2 ratio was -24.8 (95% CI -55.6 – 6.1, p = 0.12). In addition, there were no differences in either the time to discharge or in-hospital mortality between those given losartan or placebo.
Surprisingly, more patients assigned to losartan required vasopressors (20% vs 10.7%, losartan vs placebo, p = 0.08).
The authors concluded that the use of losartan in hospitalised COVID-19 patients did not produce an improvement in lung injury or clinical outcomes compared to placebo, based on an assessment of the PaO2/FiO2 ratio.
Pusharich MA et al. Efficacy of Losartan in Hospitalized Patients With COVID-19–Induced Lung Injury: A Randomized Clinical Trial JAMA Netw Open 2022