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The angiotensin receptor blocker (ARB) losartan led to hypotension and failed to improve mortality in patients hospitalized for acute COVID-19, according to the randomized, prospective -- and prematurely terminated -- ARBs CORONA II trial.

Among 341 patients in Canada and France hospitalized for acute COVID-19, 39.8% of patients who were prescribed losartan developed serious adverse events (SAEs) versus 27.2% in the usual care group (P=0.01), largely due to hypotension in the losartan arm, James Russell, MD, of the University of British Columbia in Vancouver, and colleagues reported in .

Of those prescribed losartan, 30.4% developed new-onset hypotension compared with 15.3% of patients in the usual care group (P<0.001). The findings included both ward and intensive care unit (ICU) patients.

"The increased hypotension risk suggests for the first time serious safety concerns with use of ARBs in patients hospitalized for COVID-19," the authors commented. "ARBs should probably not be added to usual care in such patients."

Russell and colleagues were unable to identify any specific markers associated with risk of hypotension.

"[ARBs] are commonly prescribed for conditions such as high blood pressure, heart disease, kidney disease, and diabetes and many of these patients are admitted to hospital with pneumonia," Russell told MedPage Today. "Doctors need to pay close attention and monitor for signs of low blood pressure and acute kidney injury in patients admitted to hospital on losartan or any other of the angiotensin receptor blockers."

"The real value of this study lies in its clear demonstration that starting an ARB during a COVID-19 infection isn't safe and doesn't improve patient outcomes," Salim Hayek, MD, a cardiologist at the University of Michigan in Ann Arbor, told MedPage Today. "While this might seem obvious in hindsight, it's crucial to have solid evidence to guide medical decisions."

"What's interesting is the extent of the problem," Hayek said, noting that researchers excluded patients at high risk, but still found that losartan caused hypotension. "This suggests that COVID-19 might make people more sensitive to blood pressure medications than expected, perhaps by unmasking the true severity of the disease," he explained.

The trial was originally designed to assess 28-day mortality among patients who received losartan, and researchers expected that the drug would prove to be safe and potentially decrease mortality in these patients, they wrote. This hypothesis was based on the fact that SARS-CoV-2 infection leads to increased angiotensin II via downregulation of angiotensin-converting enzyme 2, resulting in lung and cardiovascular inflammation and injury.

However, in April 2023, the REMAP-CAP trial found that patients hospitalized for acute COVID-19 who were prescribed ARBs or angiotensin-converting enzyme (ACE) inhibitors had increased mortality and acute kidney injury rates. Consequently, leaders of the ARBs CORONA II trial stopped the trial early and then conducted an unplanned interim analysis when results indicated poorer outcomes with losartan.

Of note, at the time the trial was stopped, there was no significant difference in the original primary outcome of 28-day mortality between the losartan group (6.5%) and the usual care group (5.9%; OR 1.11, 95% CI 0.47-2.64, P =0.81).

However, patients with hypotensive SAEs had over five times the mortality rate compared with those without hypotension in both the losartan (OR 5.37, 95% CI 1.73-16.6) and the usual care arms (OR 6.8, 95% CI 2.00-23.15).

"This study only looks at starting ARBs during a COVID-19 infection. It doesn't tell us about the effects of taking ARBs long-term before getting COVID-19," Hayek pointed out, and noted that some earlier research suggested that people already on ARBs might actually do better if they get COVID-19.

"This distinction helps explain why there's been some confusion about whether ARBs are good or bad in COVID-19. The answer may depend on when the medication is started," Hayek explained.

Use of ARBs or ACE inhibitors in patients with COVID-19 remains controversial. showed no benefit of renin angiotensin system inhibitors in managing COVID-19. And, one found that initiation of renin angiotensin system blockers increases mortality in patients with severe or critical COVID-19. However, found that among hospitalized patients with COVID-19, ACE inhibitors or ARBs were not associated with increased mortality risk, ICU admission, or mechanical ventilation.

The National Institutes of Health currently recommend that patients with COVID-19 who are receiving ARBs or ACE inhibitors should not stop taking the drugs unless discontinuation is otherwise warranted by their clinical condition.

The enrolled adults hospitalized with acute COVID-19 between October 2020 and March 2022. Exclusion criteria included acute kidney injury, hyperkalemia, hypotension, use of ARBs or ACE inhibitors within a week of presentation, pregnancy or breast feeding, among others.

Of 341 patients, 171 received losartan and 170 received usual care. Patients in the losartan group received oral losartan 25 to 100 mg/day within 72 hours of hospitalization, which was uptitrated according to treatment tolerance. Treatment with losartan or usual care continued for up to 3 months if a patient was still hospitalized. Of patients in the losartan arm, 65% were treated with 100 mg/day, the maximum dose. About 20% of patients discontinued losartan for SAEs.

The study authors also acknowledged several limitations. In addition to the trial being stopped for safety concerns, there was no placebo group. Also, mortality was lower than expected and may have been due to changes in the virulence of SARS-CoV-2 variants or to newer interventions. Losartan doses may have not been optimal and other ARBs may have proven more effective in reducing mortality, the authors noted.

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