RAS Inhibitors Flop for Critically Ill COVID

Initiation of a renin-angiotensin system (RAS) inhibitor did not improve outcomes in patients hospitalized with severe COVID-19, three randomized trials found.

In fact, the REMAP-CAP trial was terminated early because of safety concerns, while two trials from the ACTIV-4 program were stopped at the first interim analysis after failing to demonstrate a sufficient probability of efficacy; results of the trials were published in JAMA.

In REMAP-CAP, which included critically ill patients, the median number of organ support-free days was 10 for those who received an angiotensin-converting enzyme (ACE) inhibitor, 8 for those who received an angiotensin receptor blocker (ARB), and 12 in the control group, with adjusted ORs of 0.77 (95% bayesian credible interval 0.58-1.06) for ACE inhibitors and 0.76 (95% credible interval 0.56-1.05) for ARBs compared with control, reported Patrick Lawler, MD, MPH, of Toronto General Hospital, and colleagues.

The posterior probabilities that treatment worsened organ support-free days versus control were 94.9% for ACE inhibitors and 95.4% for ARBs, and the posterior probabilities that ACE inhibitors and ARBs worsened hospital survival versus control were 95.3% and 98.1%, respectively.

Hospital survival occurred in 71.9% of the ACE inhibitor group, 70.0% of the ARB group, and 78.8% of the control group, with adjusted ORs of 0.70 (95% CrI 0.44-1.06) for ACE inhibitors and 0.62 (95% CrI 0.39-0.98) for ARBs compared with control.

"Analyses suggest that there was a high probability that inhibiting angiotensin II, either by reducing its production (ACE inhibitors) or blocking its effect (ARBs), worsened outcomes among critically ill patients," Lawler and team wrote.

In two other trials from the ACTIV-4 program, results with RAS inhibitors for oxygen-free days in hospitalized patients were also negative, wrote researchers led by Wesley H. Self, MD, MPH, of Vanderbilt University Medical Center in Nashville, Tennessee.

In the first trial, RAS modulation with synthetic angiotensin (TXA-127) resulted in no difference in oxygen-free days compared with placebo, with an unadjusted mean difference of -2.3 days (aOR 0.88, 95% CrI 0.59-1.30).

In the second trial, the unadjusted mean difference in oxygen-free days was -2.4 between patients receiving angiotensin II type 1 receptor-biased ligand (TRV-027) and those receiving placebo (aOR 0.74, 95% CrI 0.48-1.13).

The secondary endpoint, 28-day all-cause mortality, was also negative, occurring in 13.5% of the TXA-127 group versus 13.3% of the placebo group (aOR 0.83, 95% CrI 0.41-1.66), and 20.6% of the TRV-027 group versus 12.9% of the placebo group (aOR 1.52, 95% CrI 0.75-3.08).

"Neither the ACTIV-4 trials nor REMAP-CAP lend any support to the hypothesis that SARS-CoV-2 infection results in harmful unopposed angiotensin II activity that might be mitigated by RAS inhibition," wrote Matthew Lee, MBChB, PhD, and John McMurray, MD, both of the British Heart Foundation Cardiovascular Research Centre at the University of Glasgow in Scotland, in an accompanying editorial.

"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," they added. "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 (e.g., heart failure)."

Lawler and his fellow REMAP-CAP researchers hypothesized that overactivation of the RAS may potentially contribute to worse COVID, and the ACTIV-4 researchers led by Self hypothesized that dysregulation of the RAS caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID pathophysiology.

In experimental models of lung injury, administration of RAS inhibitors, ACE2 inhibitors, and angiotensin 1-7 reduced pulmonary damage and mortality.

"Consequently, there has been uncertainty about the place of RAS inhibitors in patients with COVID-19," Lee and McMurray wrote in their editorial. While the results of earlier trials did not suggest harm after the initiation of RAS inhibitors, "it is unlikely that the probable harm in REMAP-CAP was specifically related to an interaction between RAS inhibition and SARS-CoV-2 infection, but rather the critical nature of the patients enrolled."

REMAP-CAP

The REMAP-CAP trial enrolled 779 adults (721 critically ill and 58 non-critically ill) hospitalized for COVID-19 at 69 centers in seven countries from March 16, 2021, to Feb. 25, 2022 (when enrollment was discontinued due to safety concerns). Median age was 56, and 35.2% were women.

Patients were randomized to receive open-label initiation of an ACE inhibitor (n=257), an ARB (n=248), an ARB combined with the chemokine receptor-2 inhibitor DMX-200 (n=10), or no RAS inhibitor (n=264) for up to 10 days.

Serious adverse events were reported in 0.9% of the ACE inhibitor group, 2.3% of the ARB group, 0% of the combined treatment group, and 1.7% of controls. One serious adverse event occurred in a non-critically ill patient in the ACE inhibitor group.

Lawler and team noted that the trial was limited by its pragmatic protocol and the fact that agents and dose equivalents varied. In addition, about one in 20 patients withdrew from the trial. Moreover, baseline characteristics of patients were imbalanced and enrollment was low overall.

ACTIV-4 Trials

Self and colleagues randomized patients with acute COVID and new-onset hypoxemia from 35 U.S. hospitals to receive one of two RAS agents as intravenous infusions for a maximum of 5 days between July 22, 2021 and April 20, 2022.

Of the 343 patients in the first trial, 170 received TXA-127 and 173 received placebo. About 66% were 31-64 years old, 58.3% were men, and 65.6% were white. Of the 290 patients in the second trial, 145 received TRV-027 and 145 received placebo. About 69% were 31-64 years old, 57.9% were men, and 67.2% were white.

The trials were limited by the fact that study drug administration was stopped at hospital discharge, with the "rationale that once a patient had clinically improved to the point of discharge, further RAS modulation would be unlikely to mitigate lung injury," Self and team noted. Longer treatment courses were not evaluated.

In addition, RAS agents were added to usual care for COVID, including corticosteroids for most patients, and their effects in combination with other treatments were not evaluated.