Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support–Free Days in Patients Hospitalized With COVID-19

Abstract

IMPORTANCEOveractivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.ObjectiveTo determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.DESIGN, SETTING, AND PARTICIPANTSIn an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).INTERVENTIONSPatients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days.MAIN OUTCOMES AND MEASURESThe primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.RESULTSOn 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).CONCLUSIONS AND RELEVANCEIn this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.TRIAL REGISTRATIONClinicalTrials.gov Identifier: NCT02735707

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

“…13,16,17,20,126,127 The REMAP-CAP trial (NCT02735707) administered either ACE inhibitors (232 patients; 35% women), conventional AT 1 R antagonists (218 patients; 30% women), or standard care (231 controls; 39% women) to COVID-19 patients with pneumonia. 128 REMAP-CAP was also terminated early as both treatments exhibited worse outcomes (survival and intensive care support) than the control group. Moreover, a significant proportion of patients on RAS blockers (>40%) discontinued treatment due to a decline in blood pressure.…”

“…Moreover, a significant proportion of patients on RAS blockers (>40%) discontinued treatment due to a decline in blood pressure. 128 Although the characterization of the NECTAR and REMAP-CAP trials regarding the status of the RAS in both females and males should be forthcoming, early termination of these RAS treatment trials does not support a critical role of the RAS (greater Ang II or reduced Ang- [1][2][3][4][5][6][7]) in the acute phase of SARS-CoV-2 infection nor explain sex differences in COVID-19 severity.…”

Response by Sipilä and Kivimäki to Letter Regarding Article, “Severe Infection and Risk of Cardiovascular Disease: A Multicohort Study”

“…Gaining insight into how treatments influence cardiovascular risk after infections is also pivotal. Although randomized trials have not shown benefits from interventions like statins, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers for patients severely ill with infection, 3,4 they indicate reduced cardiovascular complications with influenza vaccination in patients with preexisting coronary heart disease and reduced mortality with ultrashort-acting β1-blockers in treating sepsis. 5 Systematic assessment of the benefits, drawbacks, and cost-effectiveness of population-wide and targeted strategies, and personalized interventions, as well, is warranted.…”

Renin-Angiotensin System Modulation in Adults With COVID-19—Reply

“…Two of the RAS modulation strategies evaluated as potential therapeutic avenues for COVID-19 are angiotensin II type 1 receptor blockade and exogenous administration of angiotensin (1-7). Agents that block angiotensin II type 1 receptor have resulted in trends toward worse outcomes in 3 recent COVID-19 trials: for losartan in the ALPS-IP trial, for an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in the REMAP-CAP platform, and for an angiotensin II type 1 receptor–biased ligand (TRV-027) in 1 of the 2 trials reported by us (the ACTIV-4 Host Tissue Investigators). Thus, we believe that angiotensin II type 1 receptor blockade in COVID-19 does not need further study.…”