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.
Original language | English |
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Pages (from-to) | 1183-1196 |
Number of pages | 14 |
Journal | JAMA |
Volume | 329 |
Issue number | 14 |
DOIs | |
Publication status | Published - 11 Apr 2023 |
Bibliographical note
Funding Information:Funding/Support: The Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) consortium by the European Union, FP7-HEALTH-2013-INNOVATION-1 (#602525), the Rapid European COVID-19 Emergency Research response (RECOVER) consortium by the European Union’s Horizon 2020 research and innovation programme (#101003589), the Australian National Health and Medical Research Council (#APP1101719), the Health Research Council of New Zealand (#16/631), the Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant (#158584), the UK National Institute for Health and Care Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Minderoo Foundation, and the Wellcome Trust Innovations Project (215522). Dr Gordon is funded by an NIHR Research Professorship (RP-2015-06-18), Dr Shankar-Hari by an NIHR Clinician Scientist Fellowship (CS-2016-16-011), and Dr Higgins is funded by an NHMRC Emerging Leadership Fellowship (GNT2008447). In the Netherlands and EU, this domain was supported by the Dutch ZonMw grant 10430012010020. Financial assistance for the DMX-200 arm was received by Dimerix Bioscience who received funding from the Australian government via the Medical Research Future Fund Targeted Translation Research Accelerator fund.
Publisher Copyright:
© 2023 American Medical Association. All rights reserved.
Keywords
- Female
- Humans
- Male
- Middle Aged
- Angiotensin Receptor Antagonists/pharmacology
- Angiotensin-Converting Enzyme Inhibitors/pharmacology
- Bayes Theorem
- COVID-19/therapy
- Renin-Angiotensin System/drug effects
- Hospitalization
- COVID-19 Drug Treatment/methods
- Critical Illness
- Receptors, Chemokine/antagonists & inhibitors
ASJC Scopus subject areas
- General Medicine