COVID-19 Treatment Trials

USA: Initiating a renin-angiotensin system (RAS) inhibitor as a treatment for COVID-19 does not improve and likely worsens clinical outcomes in critically ill patients, according to findings from three randomized trials -- REMAP-CAP trial and two trials from the ACTIV-4 program. The trial's results were published in the Journal of the American Medical Association (JAMA).

The REMAP-CAP trial was stopped early because of safety concerns, while the other two trials were terminated at the first interim analysis after failing to demonstrate a sufficient probability of efficacy.

REMAP-CAP Trial

In the REMAP-CAP randomized clinical trial that included 779 patients (721 critically ill and 58 non–critically ill hospitalized adults), initiation of an ACE (angiotensin-converting enzyme) inhibitor or angiotensin receptor blocker, ARB (RAS inhibitors) did not improve organ support–free days (10 for those who received an ACE inhibitor, 8 for those who received an ARB and 12 in the control group). Among critically ill patients, there was a 95% probability that treatments worsened this outcome.

Key Findings

• Among 679 critically ill patients with available primary outcome data, the median age was 56, and 35.2% were women.
• Median organ support–free days among critically ill patients was 10 in the ACE inhibitor group (n = 231), 8 in the ARB group (n = 217), and 12 in the control group (n = 231) (median adjusted odds ratios of 0.77 for improvement for ACE inhibitor and 0.76 for ARB compared with control).
• The posterior probabilities that ARBs and ACE inhibitors worsened organ support–free days compared with control were 95.4% and 94.9%, respectively.
• Hospital survival occurred in 71.9% of critically ill participants in the ACE inhibitor group, 70.0% in the ARB group, and 78.8% in the control group (posterior probabilities that ARB and ACE inhibitor worsened hospital survival compared with control were 98.1% and 95.3% respectively).

"Our findings showed that initiation of an ACE inhibitor or ARB among critically ill adults with COVID-19 did not improve, and likely worsened, clinical outcomes," REMAP-CAP Investigators concluded.

ACTIV-4 Program Trials

In 2 placebo-controlled, randomized clinical trials, Wesley H. Self, Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues determined if treatment with synthetic angiotensin (1-7) (TXA-127) or an angiotensin II type 1 receptor–biased ligand (TRV-027) improve clinical outcomes in adults hospitalized with severe COVID-19.

Dr Self and colleagues reported that the number of days alive and free from supplemental oxygen during the 28 days following trial enrollment (oxygen-free days) was not significantly different from the placebo for TXA-127 or TRV-027.

Trial Details

• The two randomized clinical trials included adults hospitalized with acute COVID-19 and new-onset hypoxemia and were conducted at 35 sites in the US between 2021 and 2022; the last follow-up visit was on July 26, 2022, and reported the following findings:
• Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (65.9% aged 31-64 years, 58.3% men), 170 received TXA-127 and 173 received placebo.
• Of 290 patients in the TRV-027 trial (68.6% aged 31-64 years, 57.9% men), 145 received TRV-027 and 145 received a placebo.
• Compared with placebo, TXA-127 (unadjusted mean difference, −2.3; adjusted OR, 0.88) and TRV-027 (unadjusted mean difference, −2.4; adjusted OR, 0.74) resulted in no difference in oxygen-free days.
• In the TXA-127 trial, 28-day all-cause mortality occurred in 13.5% of patients in the TXA-127 group vs 13.3% of patients in the placebo group (adjusted OR, 0.83).
• In the TRV-027 trial, 28-day all-cause mortality occurred in 20.6% of patients in the TRV-027 group vs 12.9% in the placebo group (adjusted OR, 1.52).
• The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo.

"These findings do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for severe COVID-19 patients," Dr Self and team concluded.

References

1. Writing Committee for the REMAP-CAP Investigators. Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support–Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial. JAMA. 2023;329(14):1183–1196. doi:10.1001/jama.2023.4480
2. Self WH, Shotwell MS, Gibbs KW, et al. Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor–Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials. JAMA. 2023;329(14):1170–1182. doi:10.1001/jama.2023.3546