Effect of losartan on hospitalized patients with COVID-19-induced lung injury: A randomized clinical trial
Author:
Puskarich Michael A., Ingraham Nicholas E., Merck Lisa H, Driver Brian E, Wacker David A., Black Lauren Page, Jones Alan E., Fletcher Courtney V., South Andrew M., Nelson Andrew C.ORCID, Murray Thomas A, Tignanelli Christopher J., Lewandowski Christopher, Farhat Joseph, Benoit Justin L., Byrne Dana, Hall Alex, Reilkoff Ronald A., Biros Michelle H., Cherabuddi Kartik, Chipman Jeffrey G., Schacker Timothy W., Bold Tyler, Beckman Kenneth, Langlois Ryan, Aliota Matthew T., Guirgis Faheem W., Galbriath James, Beyer Margaret, Salmen Chas, Roberts Brian, Wright David, Voelker Helen T., Koopmeiners Joseph S.
Abstract
BackgroundSARS-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.MethodsMulticenter, 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.FindingsFrom 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.InterpretationInitiation 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.Trial RegistrationLosartan for Patients With COVID-19 Requiring Hospitalization (NCT04312009), https://clinicaltrials.gov/ct2/show/NCT04312009
Publisher
Cold Spring Harbor Laboratory
Reference40 articles.
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