Efficacy of Losartan in Hospitalized Patients With COVID-19–Induced Lung Injury
MD Michael A Puskarich, MS Nicholas E Ingraham, MD Lisa H Merck, MD, MPH Brian E Driver, MD David A Wacker, Lauren Page Black, MD, MPH Alan E Jones, MD Courtney V Fletcher, PharmD Andrew M South, MS Thomas A Murray, PhD Christopher Lewandowski, MD Joseph Farhat, MD Justin L Benoit, MD, MS Michelle H Biros, MD, MS Kartik Cherabuddi, MD Jeffrey G Chipman, MD Timothy W Schacker, MD Faheem W Guirgis, Helen T Voelker, Joseph S Koopmeiners, Christopher J Tignanelli, Andrew C Nelson, Alex Hall, David Wright, Ronald A Reilkoff, Tyler Bold, Kenneth Beckman, Ryan Langlois, Matthew T Aliota, James Galbriath, Margaret Beyer, Chas Salmen, Dana Byrne, Brian Roberts, Nastasia James
JAMA Network Open, doi:10.1001/jamanetworkopen.2022.2735
IMPORTANCE SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. OBJECTIVE To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. INTERVENTIONS Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. MAIN OUTCOMES AND MEASURES The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (PaO 2 :FiO 2 ) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental O 2 , ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensinconverting enzymes 1 and 2)] were measured in a subgroup of participants. RESULTS A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect PaO 2 :FiO 2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days).
CONCLUSIONS AND RELEVANCE This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve PaO 2 :FiO 2 ratio at 7 days. These data may have implications for ongoing clinical trials.
Author Contributions: Dr Puskarich had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Puskarich, Ingraham, Wacker, South, Murray, Biros, Chipman, Schacker, Koopmeiners, Tignanelli. Acquisition, analysis, or interpretation of data: Puskarich, Ingraham, Merck, Driver, Wacker, Black, Jones, Fletcher, South, Murray, Lewandowski, Farhat, Benoit, Biros, Cherabuddi, Guirgis, Voelker, Koopmeiners, Tignanelli. Drafting of the manuscript: Puskarich, Ingraham, Fletcher, Murray, Schacker, Koopmeiners, Tignanelli. Funding/Support: The study was primarily funded by grant No. INV-017069 from the Bill and Melinda Gates Foundation. Dr South was supported by the NIH NHLBI (grants No. K23HL148394, L40HL148910, and R01HL146818). Pharmacokinetic data analyses were supported by grant No. R01AI124965 from the NIH (Dr Fletcher).
Critical revision of the manuscript for important intellectual content
Role of the Funder/Sponsor: The funder contributed to the study design, but had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Additional Contributions: Lee Winchester, BS, and Timothy Mykris, BS (Antiviral Pharmacology Laboratory, University of Nebraska Medical Center), assisted with quantitation of losartan and carboxylosartan..
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