Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support–Free Days in Patients Hospitalized With COVID-19
Simin Aysel Florescu, Dragos Stanciu, Mihaela Zaharia, Alma Kosa, Daniel Codreanu, Komal Fareed, Aneela Kidwai, Callum Kaye, Amanda Coutts, Lynn MacKay, Charlotte Summers, Petra Polgarova, Neda Farahi, Eleonore Fox, David Sapsford, Katherine Bongaerts, Peter J Featherstone, Anthony Ng, Stephen J McWilliam, Daniel B. Hawcutt, Laura Rad, Laura O’Malley, Jennifer Whitbread, Dawn Jones, Rachael Dore, Paula Saunderson, Olivia Kelsall, Nicholas Cowley, Laura Wild, Jessica Thrush, Hannah Wood, Karen Austin, Adrian Donnelly, Martin Kelly, Naoise Smyth, Sinéad O’Kane, Declan McClintock, Majella Warnock, Ryan Campbell, Edmund McCallion, Amine Azaiz, Cyril Charron, Mathieu Godement, Guillaume Géri, Antoine Vieillard‐Baron, Paul D. R. Johnson, Shirley McKenna, Joanne Hanley, Andrew Currie, Barbara Allen, Clare McGoldrick, Moyra McMaster, Ashwin Mani, Meghena Mathew, Revathi Kandeepan, C. Vignesh, Nagarajan Ramakrishnan, Augustian James, Evangeline Elvira, Ramachandran Pratheema, Suresh Babu, Rabindrarajan Ebenezer, Sarayu Krishnamoorthy, Lakshmi Ranganathan, Manisha Ganesan, Madhu Shree, Simone Piva, Emanuele Focà, Damiano Rizzoni, Gianluca E.M. Boari, Mattia Marchesi, Magdalena Butler, Keri-Anne Cowdrey, Brittany L. Mason, Melissa Woolett, Eamon Duffy, Yan Chen, Hiromi Nakamuro, Caroline O’Connor, Lauren West, Khaled El-Khawas, Angus Richardson, Dianne Hill, Robert J. Commons, Hussam Abdelkharim, Manoj Saxena, Margaret Muteithia, Kelsey Dobell‐Brown, Rajeev Jha, Michael Kalogirou, Christine Ellis, Vinodh Krishnamurthy, Aibhilin O’Connor, Saranya Thurairatnam, Dipak Mukherjee, Agilan Kaliappan, Mark Vertue, Anne Nicholson, Joanne Riches, Gracie Maloney
Abstract
IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In 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). INTERVENTIONS: Patients 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 MEASURES: The 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. RESULTS: 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). CONCLUSIONS AND RELEVANCE: In 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 REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.