No benefit found from high-dose steroids, RAS inhibitors in latest COVID-19 trials

The results of the latest trials in inpatients with COVID-19 were negative.

The U.K.-based, international Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial reported on patients who were hospitalized with COVID-19 and had clinical evidence of hypoxia (on oxygen or oxygen saturation <92% on room air). They were randomized to either higher-dose corticosteroids (dexamethasone, 20 mg once daily for 5 days, followed by 10 mg once daily for 5 days or until discharge) (n=659) or usual care (dexamethasone, 6 mg once daily for 10 days or until discharge) (n=613). Results were published by The Lancet on April 12.

Within 28 days, 123 (19%) patients in the higher-dose group had died, compared to 75 (12%) of those getting usual care (rate ratio, 1.59 [95% CI, 1.20 to 2.10]; P=0.0012). The high-dose patients also had more pneumonia due to non-COVID-19 infection (10% vs. 6%; absolute difference, 3.7% [95% CI, 0.7% to 6.6%]) and hyperglycemia requiring increased insulin (22% vs. 14%; absolute difference, 7.4% [95% CI, 3.2% to 11.5%]). Based on these findings, the study's independent data monitoring committee recommended that the comparison be halted for patients on no or regular oxygen. The trial continues to enroll sicker patients given that “it remains an open question whether increasing the dose of corticosteroids above 6 mg dexamethasone per day is helpful for patients with COVID-19 requiring non-invasive or invasive mechanical ventilation,” the authors said. An accompanying editorial recounted the mixed research findings regarding high-dose steroids in hospitalized patients with COVID-19 and noted that “the oxygen flow rates associated with harm and benefit [from high-dose dexamethasone] cannot be defined precisely at present, but are probably greater than 10 L/min.”

In other COVID-19 research, results of the REMAP-CAP trial, published by JAMA on April 11, reported on inpatients with COVID-19 (mostly critically ill) who were randomized to an angiotensin-converting enzyme (ACE) inhibitor (n=257); an angiotensin receptor blocker (ARB) (n = 248); an ARB in combination with DMX-200, a chemokine receptor-2 inhibitor (n=10); or no RAS inhibitor (n=264) for up to 10 days. Enrollment in the trial was discontinued early when it was found that the primary outcome of organ support-free days among critically ill patients was 10 in the ACE inhibitor group, 8 in the ARB group, and 12 in the control group. The researchers calculated that the posterior probability of worsening this outcome was 94.9% for ACE inhibitors and 95.4% for ARBs. Survival to discharge was 71.9% in the ACE inhibitor group, 70.0% in the ARB group, and 78.8% in the control group. The study authors noted that the findings were inconclusive regarding non-critically ill patients and those receiving DMX-200.

Another study, also published by JAMA on April 11, reported the results of trials of investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand) in patients hospitalized with COVID-19 and new-onset hypoxemia in 2021 and 2022. Both trials met prespecified early stopping criteria for a low probability of efficacy after enrolling 343 and 290 patients, respectively. The investigational drugs were not associated with any difference in oxygen-free days or 28-day all-cause mortality. “These results suggest attempting to reverse RAS imbalances anticipated from SARS-CoV-2 infection through exogenous angiotensin (1-7) administration or blockade of the primary receptor for angiotensin II does not provide clinical benefit,” the study authors said.

An accompanying editorial summed up the findings of both studies and other research on the topic. “The totality of evidence shows that ACE inhibitors and ARBs should not be initiated as a treatment for COVID-19, especially in patients who are critically ill. Conversely, the evidence from the randomized withdrawal trials suggests that existing treatment with an RAS inhibitor does not need to be stopped in non-critically ill patients with COVID-19 if prescribed for an important indication (eg, heart failure).”