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RAS Modulation & Outcomes in Severe COVID-19

Outcomes were not improved and were probably worsened when ACE inhibitors or ARBs were started in patients hospitalized with COVID-19, the REMAP-CAP study shows. “[Renin-angiotensin system (RAS)] activation may contribute to poor clinical outcomes in patients with acute hypoxemic respiratory failure, including COVID-19,” the authors conclude. “Angiotensin II is upregulated in COVID-19 and other severe respiratory infections, proportional to severity. Inhibition of angiotensin II with ACE inhibitors or ARBs improves respiratory and other organ failure in animal models of SARS-CoV-2 infection, SARS-CoV-1 infection, sepsis, aspiration, and ventilator-induced lung injury.”

At 69 sites in 7 countries, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive a RAS inhibitor (ACE inhibitor, ARB, or ARB in combination with the chemokine-2 inhibitor DMX-200) or control for up to 10 days in an ongoing, adaptive-platform clinical trial.

Based on a primary outcome of organ support–free days (composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days), the study found: “On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).”

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 this trial 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).”

Source: JAMA