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Randomized Controlled Trial
. 2023 Apr 11;329(14):1183-1196.
doi: 10.1001/jama.2023.4480.

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial

Writing Committee for the REMAP-CAP Investigators; Patrick R Lawler  1   2 , Lennie P G Derde  3 , Frank L van de Veerdonk  4 , Bryan J McVerry  5 , David T Huang  5 , Lindsay R Berry  6 , Elizabeth Lorenzi  6 , Roland van Kimmenade  4 , Frank Gommans  4 , Muthiah Vaduganathan  7 , David E Leaf  7 , Rebecca M Baron  7 , Edy Y Kim  7 , Claudia Frankfurter  1 , Slava Epelman  1 , Yvonne Kwan  1 , Richard Grieve  8 , Stephen O'Neill  8 , Zia Sadique  8 , Michael Puskarich  9 , John C Marshall  10 , Alisa M Higgins  11 , Paul R Mouncey  12 , Kathryn M Rowan  12 , Farah Al-Beidh  13 , Djillali Annane  14   15 , Yaseen M Arabi  16 , Carly Au  12 , Abi Beane  17 , Wilma van Bentum-Puijk  3 , Marc J M Bonten  3 , Charlotte A Bradbury  18 , Frank M Brunkhorst  19 , Aidan Burrell  11 , Adrian Buzgau  11 , Meredith Buxton  20 , Maurizio Cecconi  21 , Allen C Cheng  11 , Matthew Cove  22 , Michelle A Detry  6 , Lise J Estcourt  23 , Justin Ezekowitz  24 , Mark Fitzgerald  6 , David Gattas  25 , Lucas C Godoy  1 , Herman Goossens  26 , Rashan Haniffa  27   28 , David A Harrison  12 , Thomas Hills  29 , Christopher M Horvat  30 , Nao Ichihara  31 , Francois Lamontagne  32 , Kelsey M Linstrum  5 , Daniel F McAuley  33   34 , Anna McGlothlin  6 , Shay P McGuinness  11   35 , Zoe McQuilten  11 , Srinivas Murthy  36 , Alistair D Nichol  11   37 , David R J Owen  38   39 , Rachael L Parke  35   40 , Jane C Parker  11 , Katrina M Pollock  13 , Luis Felipe Reyes  41   42 , Hiroki Saito  43 , Marlene S Santos  10 , Christina T Saunders  6 , Christopher W Seymour  5   44 , Manu Shankar-Hari  45 , Vanessa Singh  11 , Alexis F Turgeon  46   47 , Anne M Turner  29 , Ryan Zarychanski  48 , Cameron Green  11 , Roger J Lewis  6   49   50 , Derek C Angus  5   51 , Scott Berry  6 , Anthony C Gordon  13   52 , Colin J McArthur  35 , Steve A Webb  11   53
Collaborators, Affiliations
Randomized Controlled Trial

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial

Writing Committee for the REMAP-CAP Investigators et al. JAMA. .

Erratum in

  • Changes to Nonauthor Collaborator Names.
    [No authors listed] [No authors listed] JAMA. 2023 Dec 26;330(24):2398. doi: 10.1001/jama.2023.25676. JAMA. 2023. PMID: 38147102 Free PMC article. No abstract available.
  • Change to Nonauthor Collaborator Name.
    [No authors listed] [No authors listed] JAMA. 2024 Sep 17;332(11):937. doi: 10.1001/jama.2024.16951. JAMA. 2024. PMID: 39163038 Free PMC article. No abstract available.

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Lawler reported receiving grants from the Heart and Stroke Foundation of Canada during the conduct of the study and personal fees from Novartis, Brigham and Women's Hospital, CorEvitas, American College of Cardiology, and McGraw-Hill Publishing outside the submitted work. Dr Derde reported receiving grants European Union FP7 grant PREPARE (602525); EU FP7-HEALTH-2013-INNOVATION-1, grant number 602525, grants from H2020 H2020 RECOVER grant agreement No 101003589, and grants from H2020 ECRAID-Base (HORIZON-Health GRANT_NUMBER: 965313) during the conduct of the study; and being a member of the International Advisory Board Sepsis Canada, the Taskforce Acute Infectious Threats of Dutch National Intensivist Society, and chair of the ESICM Education and Training Committee. Dr McVerry reported receiving grants from Translational Breast Cancer Research Consortium and UPMC Learning While Doing Program during the conduct of the study; grants from the National Heart, Lung, and Blood Institute, Bayer Pharmaceuticals, and The Pittsburgh Foundation and personal fees from Boehringer and Synairgen Research outside the submitted work. Dr L. Berry reported receiving grants from and being an employee of Berry Consultants, which receives payments for statistical analysis and design of REMAP-CAP during the conduct of the study. Dr Lorenzi reported receiving personal fees from and being an employee of Berry Consultants, which receives payments for statistical modeling and design of REMAP-CAP during the conduct of the study. Dr van Kimmenade reported receiving grants from Novartis during the conduct of the study and personal fees from Bayer outside the submitted work. Dr Gommans reported receiving grants from ZonMw (10430012010020) during the conduct of the study. Dr Vaduganathan reported receiving personal fees from Amgen, AstraZeneca, American Regent, Baxter HealthCare, Bayer AG, Boehringer Ingelheim, Cytokinetics, Relypsa, Novartis, Roche Diagnostics, Lexicon Pharmaceuticals, Galmed, Occlutech, Impulse Dynamics, Tricog Health, NovoNordisk, and Chiesi outside the submitted work. Dr Baron reported serving on an advisory board for Merck and Genentech outside the submitted work. Dr Puskarich reported receiving grants from Bill and Melinda Gates Foundation, Minnesota Partnership for Biotechnology and Medical Genomics, and the National Institutes of Health outside the submitted work and consulting and/or serving on scientific advisory boards for Opticyte, Cytovale, and Vail Scientific for development of diagnostic devices related to sepsis. Dr Marshall reported receiving grants from the Canadian Institutes of Health Research during the conduct of the study and serving as a chair of data and safety monitoring board for AM Pharma and Adrenomed. Dr Higgins reported receiving grants from National Health and Medical Research Council and grants from The Minderoo Foundation during the conduct of the study. Dr Mouncey reported receiving grants from European Union FP7: PREPARE, Horizon 2020: ECRAID-Base, Horizon 2020: RECOVER, and the UK National Institute for Health Research during the conduct of the study. Dr Rowan reported receiving grants from the European Commission and the UK National Institute for Health and Care Research during the conduct of the study. Dr Au reported receiving grants from European Union FP7 PREPARE, Horizon 2020 ECRAID-Base, RECOVER, UK National Institute for Health and Care Research, and Monash University during the conduct of the study. Dr Beane reported receiving grants from Wellcome Trust during the conduct of the study. Dr Bradbury reported receiving personal fees for advisory, speaker fees, or conference attendance from Eli Lilly, BMS Pfizer, Bayer, Amgen, Novartis, Janssen, Portola, Ablynx, and Grifols outside the submitted work. Dr Buxton reported receiving grants from Breast Cancer Research Foundation during the conduct of the study and having contracts with Amgen and Eisai outside the submitted work. Dr Cecconi reported receiving personal fees from Edwards Lifesciences, GE HealthCare, and Draeger outside the submitted work. Dr Cove reported receiving grants from National University Health System Research Office and National Medical Research Council (Integrated innovations in infectious diseases; OFLCG19May-0034) during the conduct of the study; receiving personal fees from Medtronic and Baxter outside the submitted work; and having a patent issued for removal of carbon dioxide by dialysis (US10322221B2). Dr Detry reported receiving grants from EU Prepare European Union PREPARE consortium funding for the statistical design and analysis of REMAP-CAP trial to Berry Consultants, grants from Australian National Health and Medical Research Council (#APP1101719) Australian funding for the statistical design and analysis of REMAP-CAP trial to Berry Consultants, grants from Health Research Council of New Zealand New Zealand funding for the statistical design and analysis of REMAP-CAP trial to Berry Consultants, and grants from University of Pittsburgh Medical Center (UPMC) US funding from Learning While Doing Program for the statistical design and analysis of REMAP-CAP trial to Berry Consultants during the conduct of the study. Dr Estcourt reported receiving grants from National Institute for Health and Care Research and European Union Horizon 2020 outside the submitted work. Dr Ezekowitz reported receiving grants from Bayer, Merck, Novartis, Novo Nordisk, Otsuka, Applied Therapeutics, AstraZeneca, and Boeringher Ingelheim outside the submitted work. Dr Fitzgerald reported receiving grants from PREPARE Network, European Commission Statistical design and analysis of the REMAP-CAP trial, grants from OPTIMISE-CAP, Australia Funding Statistical design and analysis of the REMAP-CAP trial, grants from REMAP-CAP, New Zealand Funding Statistical design and analysis of the REMAP-CAP trial, and grants from GCAR, United States Funding Statistical design and analysis of the REMAP-CAP trial during the conduct of the study. Dr Godoy reported receiving the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the Canadian Institutes of Health Research. Dr Haniffa reported receiving grants from Wellcome Trust, Medical Research Council/UK Research and Innovation, and Canadian Institutes of Health Research during the conduct of the study and grants from ICODA, Wellcome Trust, and National Institute for Health and Care Research outside the submitted work. Dr Harrison reported receiving grants from European Union FP7 (PREPARE) and Horizon 2020 (ECRAID-Base and RECOVER), UK National Institute for Health and Care Research, and Monash University during the conduct of the study. Dr Hills reported receiving grants from Health Research Council of New Zealand during the conduct of the study. Dr Horvat reported receiving grants from Eunice Kennedy Shriver National Institute of Child Health and Human Development during the conduct of the study. Dr McAuley reported receiving grants from National Institute for Health and Care Research Health Technology Assessment during the conduct of the study; personal fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, and Vir Biotechnology and grants from Wellcome Trust , National Institute for Health and Care Research, Innovate UK, MRC, and Northern Ireland HSC Research and Development Division outside the submitted work; and having a patent for anti-inflammatory treatment issued to Queen's University Belfast for novel treatment for inflammatory disease (US8962032) and being co-director for research for the Intensive Care Society and NIHR/MRC Efficacy and Mechanism Evaluation Programme. Dr McGlothlin reported receiving grants reported receiving grants from EU Prepare European Union PREPARE consortium funding for the statistical design and analysis of REMAP-CAP trial to Berry Consultants, grants from Australian National Health and Medical Research Council (#APP1101719) Australian funding for the statistical design and analysis of REMAP-CAP trial to Berry Consultants, grants from Health Research Council of New Zealand funding for the statistical design and analysis of REMAP-CAP trial to Berry Consultants, and grants from University of Pittsburgh Medical Center (UPMC) US funding from Learning While Doing Program for the statistical design and analysis of REMAP-CAP trial to Berry Consultants during the conduct of the study. Dr Murthy reported receiving grants from the Canadian Institutes of Health Research and Health Research Foundation during the conduct of the study. Dr Nichol reported receiving grants from Health Research Board of Ireland during the conduct of the study. Dr Parke reported receiving grants from Fisher and Paykel Healthcare paid to the institution outside the submitted work. Dr Pollock reported Imperial College London receiving funding from the European Commission through the PREPARE FP7 grant (number 602525) during the conduct of the study; and grants from MRC/UKRI MRC (MR/W024977/1 ), Chan Zuckerberg Initiative, Trevena, Imperial, British Heart Foundation, grants from MRC/UKRI, European Commission Horizon 2020 European AIDS Vaccine Initiative 2020, and MRC/UKRI and personal fees from Sanofi Pasteur, Seqirus, and Moderna outside the submitted work. Dr Reyes reported receiving grants and personal fees from Merck and personal fees from Pfizer and GSK outside the submitted work. Dr Saunders reported receiving grants from PREPARE Network, OPTIMISE-CAP, and REMAP-CAP during the conduct of the study. Dr Seymour reported receiving grants from NIH/NIGMS during the conduct of the study and personal fees from Inotrem and Beckman Coulter outside the submitted work. Dr Shankar-Hari reported being funded by a clinician scientist fellowship (2016-16-011) from the National Institute for Health and Care Research; receiving grants from the Chief Scientists Office Scotland for time-critical precision medicine in critically ill adult patients (TRAITS Programme) and highlights industry support for TRAITS research programme (https://www.ed.ac.uk/inflammation-research/clinical-trials/traits-ci-trial). Dr Turgeon reported receiving grants from Canadian Institutes of Health Research during the conduct of the study. Dr Turner reported receiving grants from Health Research Council of New Zealand during the conduct of the study. Dr Lewis reported being the senior medical scientist at Berry Consultants, a statistical consulting firm that specializes in the design, implementation, oversight, and interpretation of bayesian adaptive and platform clinical trials. Dr Angus reported receiving grants from Breast Cancer Research Foundation and grants from the National Institutes of Health during the conduct of the study. Dr S. Berry reported being part owner of Berry Consultants, which received fees for trial design and analysis during the conduct of the study. Dr Gordon reported receiving grants from NIHR Research Professorship (RP-2015-06-18) and grants from NIHR REMAP-CAP trial during the conduct of the study and personal fees from 30 Respiratory, AstraZeneca, Janssen, and Novartis and and grants from NIHR Imperial BRC outside the submitted work. Dr McArthur reported receiving grants from Health Research Council of New Zealand during the conduct of the study. Dr Webb reported receiving grants from National Health and Medical Research Council, Medical Research Future Fund, and Minderoo Foundation during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Participants in a Study of the Effect of Angiotensin-Converting Enzyme (ACE) Inhibitor and Angiotensin Receptor Blocker (ARB)
aCould meet >1 exclusion criterion (Supplement 1). bConcern for clinically relevant hypotension or escalation of vasopressor requirements, hyperkalemia, severe renal artery stenosis, pregnancy or breastfeeding, and, for ARB and DMX-200, severe liver disease or alanine transaminase or aspartate transaminase >5 times the upper limit of normal, known viral hepatitis, or hypersensitivity to repagermanium. cVia centralized computer program with balanced assignment based on the number of interventions per site. dReceiving respiratory or cardiovascular organ support. eAvailable later than ACE inhibitor and ARB interventions at a subset of sites. fThe primary analysis in the RAS domain is estimated from a model that adjusts for patient factors and randomization to other interventions; all patients enrolled in the COVID-19 cohort with consent and follow-up are included. The final estimate of an intervention’s effectiveness relative to any other in that domain is generated from patients who could have been randomized to either.
Figure 2.
Figure 2.. Organ Support–Free Days Up to Day 21 in Critically Ill Patients
A, Curves that increase more gradually are more favorable. B, See eFigure 1 in Supplement 2 for the primary outcome distribution for the 6 critically ill patients randomized to the combined ARB and DMX-200 intervention and eFigure 2 in Supplement 2 for the 56 non–critically ill patients. ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
Figure 3.
Figure 3.. Survival Through 90 Days in Critically Ill Patients and Treatment Effects on Hospital Survival
A, Patients who did not die within 90 days are censored at day 90 with no event. B, Ranked estimated individual-level conditional average treatment effect on hospital survival for all patients is shown. From the final causal forest on hospital survival pooling both angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) interventions, treatment effect in tree terminal leaves with each individual’s control and intervention neighbors are combined to give an estimate of individual-level treatment effect conditional on their baseline covariates. Ranked absolute risk difference estimate with its 95% CI is shown for each.
See this image and copyright information in PMC

Comment in

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