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Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support–free days in patients hospitalized with COVID-19

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Title: Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support–free days in patients hospitalized with COVID-19
Authors: Writing Committee for the REMAP-CAP Investigators
Lawler, PR
Derde, LPG
Van de Veerdonk, FL
McVerry, BJ
Huang, DT
Berry, LR
Lorenzi, E
Van Kimmenade, R
Gommans, F
Vaduganathan, M
Leaf, DE
Baron, RM
Kim, EY
Frankfurter, C
Epelman, S
Kwan, Y
Grieve, R
O'Neill, S
Sadique, Z
Puskarich, M
Marshall, JC
Higgins, AM
Mouncey, PR
Rowan, KM
Al-Beidh, F
Annane, D
Arabi, YM
Au, C
Beane, A
Van Bentum-Puijk, W
Bonten, MJM
Bradbury, CA
Brunkhorst, FM
Burrell, A
Buzgau, A
Buxton, M
Cecconi, M
Cheng, AC
Cove, M
Detry, MA
Estcourt, LJ
Ezekowitz, J
Fitzgerald, M
Gattas, D
Godoy, LC
Goossens, H
Haniffa, R
Harrison, DA
Hills, T
Horvat, CM
Ichihara, N
Lamontagne, F
Linstrum, KM
McAuley, DF
McGlothlin, A
McGuinness, SP
McQuilten, Z
Murthy, S
Nichol, AD
Owen, DRJ
Parke, RL
Parker, JC
Pollock, KM
Reyes, LF
Saito, H
Santos, MS
Saunders, CT
Seymour, CW
Shankar-Hari, M
Singh, V
Turgeon, AF
Turner, AM
Zarychanski, R
Green, C
Lewis, RJ
Angus, DC
Berry, S
Gordon, AC
McArthur, CJ
Webb, SA
Item Type: Journal Article
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.
Issue Date: 11-Apr-2023
Date of Acceptance: 7-Mar-2023
URI: http://hdl.handle.net/10044/1/104002
DOI: 10.1001/jama.2023.4480
ISSN: 0098-7484
Publisher: American Medical Association
Start Page: 1183
End Page: 1196
Journal / Book Title: JAMA: Journal of the American Medical Association
Volume: 329
Issue: 14
Copyright Statement: © 2023 American Medical Association. All rights reserved.
Publication Status: Published
Conference Place: United States
Online Publication Date: 2023-04-11
Appears in Collections:Department of Surgery and Cancer
Department of Infectious Diseases
Imperial College London COVID-19
Department of Brain Sciences