Effect of losartan on hospitalized patients with COVID-19-induced lung injury: A randomized clinical trial

Puskarich, M. A.; Ingraham, N. E.; Merck, L. H.; Driver, B. E.; Wacker, D. A.; Black, L. P.; Jones, A. E.; Fletcher, C. V.; South, A. M.; Nelson, A. C.; Murray, T. A.; Lewandowski, C.; Farhat, J.; Benoit, J. L.; Bryne, D.; Hall, A.; Reilkoff, R. A.; Biros, M. H.; Cherabuddi, K.; Chipman, J. G.; Schacker, T. W.; Bold, T.; Beckman, K. B.; Langlois, R.; Aliota, M.; Guirgis, F.; Galbraith, J.; Beyer, M.; Salmen, C.; Roberts, B. W.; Wright, D. W.; Voelker, H.; Koopmeiners, J. S.; Tignanelli, C. J.

Background: SARS-CoV-2 viral entry may disrupt angiotensin II (Ang II) homeostasis in part via ACE2 downregulation, potentially contributing to COVID-19 induced lung injury. Preclinical models of viral pneumonias that utilize ACE2 demonstrate Ang II type 1 receptor (AT1R) blockade mitigates lung injury, though observational COVID-19 data addressing the effect of AT1R blockade remain mixed. Methods: Multicenter, blinded, placebo-controlled randomized trial of losartan (50 mg PO twice daily for 10 days) versus placebo. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already taking a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible. The primary outcome was the imputed partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity, oxygen, ventilator, and vasopressor-free days, and mortality. Losartan pharmacokinetics (PK) and RAAS components [Ang II, angiotensin-(1-7) (Ang-(1-7)), ACE, ACE2] were measured in a subgroup of participants. Findings: From April 2020 - February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO2/FiO2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0.12)]. Losartan did not improve any secondary clinical outcome, but worsened vasopressor-free days. PK data were consistent with appropriate steady-state concentrations, but we observed no significant effect of losartan on RAAS components. Interpretation: Initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury does not improve PaO2 / FiO2 ratio at 7 days. These data may have implications for ongoing clinical trials.