Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: A Randomized Clinical Trial

Abstract

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 (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting 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 Pao2:Fio2 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 Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials.

Trial registration: ClinicalTrials.gov Identifier: NCT04312009.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Puskarich reported receiving grants from Minnesota Partnership for Biotechnology and Medical Genomics and personal fees from the National Institutes of Health (NIH) Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies Network outside the submitted work. Dr Merck reported receiving grants from NIH outside the submitted work. Dr Black reported receiving grants from National Center for Advancing Translational Sciences (NCATS) and National Institute of General Medical Sciences (NIGMS) outside the submitted work. Dr Fletcher reported receiving grants from the National Institute of Allergy and Infectious Diseases during the conduct of the study. Dr South reported receiving grants from the NIH National Heart, Lung, and Blood Institute (NHLBI) outside the submitted work. Dr Cherabuddi reported receiving grants from Merck, National Institute of Allergy and Infectious Diseases, and Biomedical Advanced Research and Development Authority outside the submitted work. Dr Tignanelli reported receiving grants from Minnesota Partnership for Biotechnology and Medical Genomics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Participant Recruitment Flowchart

ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II type 1 receptor blocker; eGFR, estimated glomerular filtration rate; LAR, legally authorized representative; LFT, liver function test; and SOFA, sequential organ failure assessment.

Figure 2.. Arterial Partial Pressure of Oxygen to Fraction of Inspired Oxygen (Pao2:Fio2) Ratios for Losartan and Placebo Groups

Figure 3.. Cumulative Incidence of Death and Discharge in Losartan and Placebo Groups

Solid lines indicate death; dotted lines, discharge.