The administration of losartan to hospitalized COVID-19 patients with acute lung injury did not improve their lung function, according to the results of a randomized clinical trial from the Angiotensin Receptor Blocker Based Lung Protective Strategies for Inpatients With COVID-19 (ALPS-IP) Investigators.
The investigators had hoped to see benefit with losartan, as preclinical models had demonstrated that angiotensin II type 1 receptor blockade mitigated lung injury, but those hopes were dashed with the negative results.
"The main take-home message is that losartan 50 mg orally twice-daily does not reduce lung injury in moderate to severe COVID-19 as we initially hypothesized, but still carries the expected known risks of the drug," lead author Michael Puskarich, MD, Department of Emergency Medicine, University of Minnesota, Minneapolis, told theheart.org | Medscape Cardiology.
The findings were published in the March issue of JAMA Network Open.
Puskarich said the study was conceptualized in the early days of the pandemic, when COVID-19 was still primarily limited to Wuhan.
"Chinese investigators reported excessive, dysregulated angiotensin II levels in patients with severe lung injury from COVID-19. Following the SARS outbreak in the early 2000s, preclinical studies showed that virus entered into cells through the ACE2 receptor, which led to high angiotensin II levels, similar to what was described by scientists in China in patients with COVID-19," he said.
When rodents infected with SARS were treated with losartan, it helped to fix this disrupted signalling and reduced lung injury, as well as mortality.
"Given that the SARS-CoV-2 virus responsible for COVID-19 entered cells via the same ACE2 receptor, we thought losartan may be effective in humans the same way it was effective in rodents with SARS," Puskarich said.
He acknowledged that the ALPS-IP investigators were disappointed to see no treatment effect.
"A widely available, fairly safe generic drug with efficacy against COVID-19 would have been very useful globally, given supply shortages and costs associated with many of the novel therapies for COVID-19," Puskarich said.
The blinded, placebo-controlled randomized trial was conducted in 13 hospitals across the United States from April 2020 to February 2021 and included a racially and ethnically diverse population.
A total of 205 patients (mean age, 55.2 years; 60% male) with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 who were naïve to renin-angiotensin-aldosterone system (RAAS) inhibitors were included in the trial.
The patients were given losartan 50 mg orally twice-daily (n = 101) or placebo (n = 104) for 10 days or until discharge from the hospital.
Losartan did not significantly improve lung injury, as measured by the partial pressure of oxygen to fraction of inspired oxygen (Pa02:Fi02) ratio at 7 days (difference, –24.8; 95% CI, –55.6 to 6.1; P = .12). Nor did losartan reduce mortality, ventilator-free days, or oxygen-free days.
However, patients receiving losartan had fewer vasopressor-free days than those receiving placebo (8.7 vs 9.4 days).
In addition, the trial showed two potentially harmful effects of losartan on hemodynamics and kidney function.
Puskarich said he hopes that the negative result of the trial does not inhibit or prevent studies of repurposed, inexpensive, and well-tolerated drugs to continue, not just for COVID-19, but for other global health conditions.
"Investigators and data safety monitoring boards of ongoing trials of commercially available and investigational agents targeting the renin-angiotensin-aldosterone system for COVID-19 should at least be aware of these data. Each trial should individually assess whether these data influence the safety profile of their ongoing studies and decide if changes to their protocol are indicated," he added.
"However, changes in patient demographics, variants, and cotreatment parameters may differ between our study and others, making broad generalizations difficult."
The study was funded by the Bill and Melinda Gates Foundation. Puskarich reports 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.
JAMA Netw Open. 2022;5(3):e222735. Full text
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