In a pair of trials stopped early for lack of efficacy, the use of investigational agents for potentiation of the angiotensin (1-7) pathway and mitigation of the angiotensin II pathway did not improve clinical outcomes among adults hospitalized with COVID-19–associated hypoxemia. The renin-angiotensin system (RAS) modulators, TXA-127 and TRV-027, are synthetic angiotensin (1-7) and an angiotensin II type 1 receptor-based ligand, respectively.
At 35 U.S. sites in 2021–22, adults hospitalized with acute COVID-19 and new-onset hypoxemia were randomized to an active agent or placebo in an m:1 ratio as part of the fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) program, with m representing the number of trials the patient was eligible for (1 or 2). Active treatments were a 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or a 12-mg/h continuous intravenous infusion of TRV-027 for 5 days.
An ordinal outcome, oxygen-free days, classified a patient’s status at day 28 based on mortality and duration of supplemental oxygen use (an adjusted odds ratio [OR] greater than 1.0 indicated the superiority of the RAS agent vs. placebo). The results were as follows: “Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, −2.3 [95% CrI, −4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, −2.4 [95% CrI, −5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo.”
Editorial: “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,” editorialists write, referring to these trials and a related article in this issue of JAMA. “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).”