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. 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
PMCID: PMC10326520  PMID: 37039790

Key Points

Question

Does initiating an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in adult patients hospitalized for COVID-19 improve organ support–free days (a composite of hospital survival and duration of intensive care respiratory or cardiovascular support)?

Findings

In this randomized clinical trial that included 779 patients, initiation of an ACE inhibitor or ARB did not improve organ support–free days. Among critically ill patients, there was a 95% probability that treatments worsened this outcome.

Meaning

Among critically ill patients, initiation of an ACE inhibitor or ARB as treatment for COVID-19 did not improve, and likely worsened, clinical outcomes.

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

This randomized clinical trial examines the effect of initiation of a renin-angiotensin system inhibitor (ACE inhibitor or an angiotensin receptor blocker) on the composite outcome of hospital survival and organ support through 21 days in hospitalized patients with COVID-19.

Introduction

Angiotensin-converting enzyme 2 (ACE2), a central regulator of the renin-angiotensin system (RAS), is expressed in the respiratory epithelium and vascular endothelium and is the human host receptor for the SARS-CoV-2 virus.1,2 Disruption of ACE2 activity due to viral binding, and other mechanisms, may upregulate angiotensin II in patients with COVID-19.3,4,5,6,7 Angiotensin II promotes inflammation, activates coagulation, increases capillary permeability, upregulates fibrotic responses, and causes vasoconstriction that may contribute to microcirculatory dysfunction and ventilation/perfusion mismatch.3,8,9,10 These pathogenic responses characterize severe COVID-19 and therefore, attenuating angiotensin II may improve outcomes. This hypothesis is supported by observational and experimental studies in COVID-1911,12 and other studies in acute lung injury due to SARS-CoV-1, sepsis, aspiration, and ventilator-induced lung injury.7,13,14,15 Given the direct interaction between the RAS and SARS-CoV-2, attenuating angiotensin II may be particularly beneficial in COVID-19.

In an ongoing adaptive platform trial, the effect of new initiation of an RAS inhibitor (either an ACE inhibitor or an angiotensin receptor blocker [ARB]) on the composite outcome of hospital survival and organ support provision through 21 days was evaluated in patients hospitalized with COVID-19 pneumonia.

Methods

Trial Design and Oversight

The ACE2 RAS domain is one of multiple therapeutic domains in the Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial (NCT02735707). REMAP-CAP is an international, adaptive platform randomized clinical trial16,17 evaluating treatments for severe pneumonia. Trial design details have been previously published18 and are available in Supplement 1. Patients are assessed for platform eligibility and potentially randomized to receive 1 or more interventions among available domains, organized by therapeutic areas. The trial previously reported the effects of corticosteroids, anticoagulants, antivirals, IL-6 receptor antagonists, convalescent plasma, and antiplatelet agents in patients with COVID-19.19,20,21,22,23,24,25 The trial was approved by regional ethics committees and conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Written or verbal informed consent was obtained from all patients or their surrogates in accordance with local legislation.

Participants

Patients 18 years or older hospitalized with clinically suspected or microbiologically confirmed COVID-19 pneumonia were eligible for inclusion (Figure 1). Patients were stratified into critically ill and non–critically ill groups at enrollment. Patients receiving respiratory (high-flow nasal oxygen with flow rate ≥30 L/min and fraction of inspired oxygen ≥0.4 or noninvasive or invasive mechanical ventilation) or cardiovascular (vasopressor/inotrope) organ support in an intensive care unit (ICU) were considered critically ill. All other hospitalized patients were considered non–critically ill. Critically ill patients were eligible for enrollment within 48 hours of ICU admission and non–critically ill patients were eligible within 96 hours of hospital admission. Patients were excluded on the basis of long-term or current RAS inhibitor use or known intolerance, risk of clinically relevant hypotension or escalation of vasopressor requirements, hyperkalemia, severe kidney impairment, severe renal artery stenosis, or pregnancy or breastfeeding. Detailed domain and platform eligibility are presented in eAppendix 1 in Supplement 2. In view of racial and ethnic differences in outcomes during the pandemic, self-reported race and ethnicity were collected from participants or their surrogates via fixed categories appropriate to their region at approving sites.

Figure 1. Flow of Participants in a Study of the Effect of Angiotensin-Converting Enzyme (ACE) Inhibitor and Angiotensin Receptor Blocker (ARB) .

Figure 1.

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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.

Treatment Randomization

All participating sites randomized patients to receive control (no RAS inhibitor) and up to 3 active interventions, including ACE inhibitor, ARB, and, at a subset of participating sites, an ARB in combination with DMX-200. DMX-200 is an investigational oral chemokine receptor-2 antagonist targeting macrophage chemotaxis given in combination with an ARB due to putative synergistic anti-inflammatory effects. Computerized randomization was performed centrally with balanced, fixed randomization ratios based on the number of available interventions at each site. Response-adaptive randomization was not used in this domain. Patients could also be randomized to receive interventions in other domains depending on availability and eligibility.

Interventions

Treatment assignments included initiation of and in-hospital treatment with an enterally administered ACE inhibitor, ARB, ARB in combination with DMX-200, or control (no initiation of an RAS inhibitor). Sites selected from a hierarchical list of ACE inhibitors and ARBs (Supplement 1) to encourage consistency in study agent while permitting flexibility based on drug availability and experience. All treatments were open-label. Initial dosing and subsequent titration were determined by the treating clinician, with guidance provided in the protocol (Supplement 1). The protocol advised discontinuing the study drug in patients with clinically-relevant hypotension or escalating vasopressor requirements, hyperkalemia, declining kidney function, severe kidney impairment, exposure to nephrotoxic agents, angioedema (in the ACE inhibitor group), and liver failure or hepatic transaminase elevation or other possible adverse reaction (in the combination ARB and DMX-200 group). Treatment was continued for up to 10 days or until hospital discharge, whichever occurred first. Patients in the control group received no RAS inhibitor absent developing a specific indication for one.

Outcome Measures

The primary outcome was organ support–free days. In this composite ordinal outcome, all deaths that occurred during the index hospitalization were assigned the worst possible outcome (–1). Among survivors, respiratory and cardiovascular organ support–free days were calculated through day 21 (survivors with no organ support were assigned a score of 22). Higher scores indicate better outcomes. In REMAP-CAP, this hospital-based outcome correlates with longer-term outcomes.26

Prespecified secondary outcomes included hospital survival, survival at 90 days, ventilator-free days, vasopressor-/inotrope-free days, duration of hospital and ICU stays, World Health Organization COVID-19 severity scale score at day 14, hypotension while admitted to a hospital ward, angioedema, change from baseline to peak creatinine, kidney replacement–free days, severe adverse events, and acute kidney injury (AKI) ascertained through postrandomization days 7 and 14 using the modified Kidney Disease Improving Global Outcomes criteria for stage 2 or 3 kidney injury (see eAppendix 1 in Supplement 2). For the combined ARB and DMX-200 intervention, additional secondary safety outcomes included change from baseline to peak hepatic transaminases as well as occurrence of suspected unexpected serious adverse reactions. All outcomes were site reported and not adjudicated.

Statistical Analysis

This domain employed an adaptive 2-stage design with an initial evaluation period given limited experience with the study treatments in critically ill patients (eFigure 1 in Supplement 2). During the evaluation period, interventions were required to demonstrate an acceptable safety profile as judged by the data and safety monitoring board and an intermediate probability of efficacy, defined as at least 50% posterior probability of at least 20% improvement in the proportional odds ratio (OR) for organ support–free days for ACE inhibitor and ARB initiation compared with control or at least 30% for the combined ARB and DMX-200 intervention compared with both ARB and control to proceed to stage 2. Stage 1 was planned up to maximum sample sizes of 300 patients in each of the ACE inhibitor and ARB groups and 200 patients in the combined ARB and DMX-200 intervention group. Graduation rules were prespecified and would be implemented in a blinded fashion. Interventions that satisfied graduation criteria would continue to the uncapped evaluative period, which would enroll until platform-level adaptive stopping triggers for efficacy (posterior probability >99% of OR >1.0 compared with control) or futility (posterior probability >95% of OR <1.2 compared with control) were reached. The futility trigger could be reached at any adaptive analysis. Interventions failing to graduate would be withdrawn in stage 1. Enrollment was closed in stage 1 for safety concerns prior to an adaptive analysis being performed.

The primary analysis was an intention-to-treat analysis and included all consenting patients with suspected or proven COVID-19 with available primary outcome. The primary analysis was a bayesian cumulative logistic model adjusted for age, sex, site, and enrollment period (in 2-week intervals), and included covariates reflecting intervention and domain eligibility. Treatment effects were estimated only from patients randomized in the domain. Patients with COVID-19 enrolled in REMAP-CAP but outside of this domain did not contribute to estimates of RAS inhibitor effects, but did contribute to overall model covariate coefficient estimation.

The primary model was fit using a Markov chain Monte Carlo algorithm with 20 000 samples from the joint posterior distribution. The model calculated posterior distributions for the proportional OR, including medians and 95% credible intervals (CrIs), and the posterior probabilities of efficacy for each intervention compared with control. The probability of harm is the complement of the probability of efficacy (ie, posterior probability OR <1.0). Distinct treatment effects were estimated in critically ill and non–critically ill patients by nesting intervention effects in a hierarchical prior distribution centered on an overall intervention effect estimated with a neutral prior; the posterior distributions for these effects were shrunk toward the overall estimate to an extent reflective of their similarity (dynamic borrowing).27

Secondary analyses were performed using bayesian logistic regression models for ordinal and dichotomous outcomes, bayesian linear models for continuous outcomes, and bayesian piecewise exponential models for time-to-event outcomes. No formal hypothesis tests were performed on secondary outcomes, and summaries of posterior distributions are provided for descriptive purposes only. Sensitivity and other secondary analyses were performed by investigators blinded to ongoing interventions and did not include adjustment for treatment assignment in ongoing domains.

Prespecified subgroup analyses assessed treatment effect by age (<50, 50-70, or >70 y), sex, baseline invasive mechanical ventilation status, estimated glomerular filtration rate (<90 mL/min/1.73 m2, ≥90 mL/min/1.73 m2, or unknown), and baseline vasopressor receipt. Machine learning with causal forests28,29 estimated subgroup- and individual-level heterogeneity of treatment effects by considering all available baseline covariates in separate and pooled treatment analyses. Expected absolute risk differences were estimated for conditional average treatment effects at the levels of the individual and the subgroup (see eAppendix 1 in Supplement 2).

Analysis details are provided in the statistical analysis plan in Supplement 1. The primary and key secondary analyses were performed using R, version 4.1.3 (R Foundation). The causal forests heterogeneity of treatment effect analyses were conducted using R, version 4.0.5, with the R package grf, version 2.1.0.

Results

Enrollment and Participant Characteristics

The first patient was enrolled in the ACE2 RAS domain on March 16, 2021. On February 25, 2022, enrollment of critically ill patients was discontinued on advice from the data and safety monitoring board due to concern for higher mortality and AKI in the ACE inhibitor and ARB groups compared with the control group based on a scheduled assessment of safety data from 564 patients. Enrollment of non–critically ill patients was concurrently paused and subsequently discontinued on June 8, 2022, by the trial steering committee due to the findings in critically ill patients and slow recruitment.

A total of 721 critically ill patients and 58 non–critically ill patients were randomized (Figure 1) at 69 sites in 7 countries (Canada, Italy, Netherlands, New Zealand, Saudi Arabia, United Kingdom, and US). Of these individuals, 34 critically ill and 2 non–critically ill patients withdrew consent, and outcomes were unavailable for 2 critically ill patients. Baseline characteristics were similar between the groups, although some imbalances were present, including vasopressor receipt (Table 1 and eTable 2 in Supplement 2). Ramipril was the most common ACE inhibitor and losartan was the most common ARB used, at low or moderate doses (see eTable 1 in Supplement 2 for dose classifications), for median treatment durations of 6 days for ACE inhibitors and 7 days for ARBs in critically ill patients and 2 days for ACE inhibitors and 5 days for ARBs in non–critically ill patients (eTable 3 in Supplement 2). Among patients randomized to receive an ACE inhibitor or ARB, 104 of 243 (42.8%) in the ACE inhibitor group and 132 of 236 (55.9%) in the ARB group did not complete the full treatment course, commonly due to hypotension (eTable 4 in Supplement 2).

Table 1. Characteristics of Critically Ill Participants at Baselinea.

Characteristic Median (IQR) [total No.]
ACE inhibitor (n = 232) ARB (n = 218) Control (n = 231)
Age, y 55.0 (43.0-66.0) 55.5 (44.0-63.0) 56.0 (44.0-65.0)
Women, No. (%) 82 (35.3) 66 (30.3) 91 (39.4)
Men, No. (%) 150 (64.7) 152 (69.7) 140 (60.6)
Race and ethnicity, No./total No. (%)b
Asian 7/146 (4.8) 7/142 (4.9) 8/140 (5.7)
Black 6/146 (4.1) 11/142 (7.7) 9/140 (6.4)
Mixed or multiple races or ethnicities 0/146 (0.0) 3/142 (2.1) 2/140 (1.4)
White 126/146 (86.3) 114/142 (80.3) 114/140 (81.4)
Other 7/146 (4.8) 7/142 (4.9) 7/140 (5.0)
Body mass index 30.3 (26.4-36.9) [210] 30.1 (27.2-37.2) [200] 30.5 (27.3-35.8) [213]
APACHE II scorec 11.0 (6.0-17.0) [231] 10.0 (7.0-14.0) [217] 10.0 (6.0-16.0) [230]
Clinical Frailty Scale scored 2.0 (2.0-3.0) [228] 2.0 (2.0-3.0) [215] 2.0 (2.0-3.0) [229]
Confirmed SARS-CoV-2 infection, No./total (%)e 202/207 (97.6) 189/191 (99.0) 198/199 (99.5)
Preexisting condition, No./total No. (%)f
Diabetes 35/231 (15.2) 31 (14.2) 29 (12.6)
Respiratory disease 45/230 (19.6) 43/217 (19.8) 51/229 (22.3)
Kidney disease 7/205 (3.4) 2/209 (1.0) 2/213 (0.9)
Severe cardiovascular disease 9/231 (3.9) 9 (4.1) 5/228 (2.2)
Any immunosuppressive condition 12/230 (5.2) 13/217 (6.0) 15/229 (6.6)
Time to enrollment from hospital admission, median (IQR), d 2.0 (1.1-3.7) 2.0 (1.1-3.9) 2.1 (1.1-3.8)
Time to enrollment from ICU admission, h 17.7 (8.9-27.0) (n = 231) 16.9 (7.3-23.4) 16.2 (6.5-23.8)
Acute respiratory support, No. (%)
Invasive mechanical ventilation 73/231 (31.6) 62 (28.4) 66 (28.6)
Noninvasive ventilation only 91/231 (39.4) 83 (38.1) 85 (36.8)
High-flow nasal cannula 68/231 (29.4) 73 (33.5) 81 (35.1)
None/supplemental oxygen 0/231 (0.0) 0 0
Pao2/FiO2g 122.0 (88.0-158.0) [225] 112.0 (83.5-151.0) [215] 121.0 (91.0-154.8) [222]
Systolic blood pressure, mm Hg 126.0 (114.0-144.0) [227] 128.0 (115.0-145.0) [215] 130.0 (115.0-144.2) [228]
Vasopressor support, No. (%) 43 (18.6) 30 (13.8) 28 (12.1)
Extended Cardiovascular SOFA scoreh 0.0 (0.0-0.0) [230] 0.0 (0.0-0.0) [217] 0.0 (0.0-0.0) [229]
Laboratory valuesi
C-reactive protein, μg/mL 92.0 (34.0-157.0) [205] 76.0 (37.0-146.0) [187] 91.5 (37.8-162.8) [186]
Lactate, mmol/L 1.3 (1.0-1.9) [201] 1.3 (1.0-1.7) [197] 1.3 (1.0-1.6) [211]
Creatinine, mg/dL 0.8 (0.6-1.0) [231] 0.7 (0.6-0.9) [217] 0.7 (0.6-0.9) [228]
eGFR, min/min/1.73 m2 100.8 (86.0-113.7) [231] 103.5 (92.4-113.4) [217] 102.9 (92.8-115.9) [228]
Potassium, mmol/L 4.3 (4.1-4.6) [222] 4.2 (4.0-4.5) [210] 4.2 (3.9-4.5) [219]
Concomitant therapies, No./total No. (%)j
Remdesivir 34/228 (14.9) 34/217 (15.7) 39/230 (17.0)
Corticosteroids 226/228 (99.1) 214/217 (98.6) 226/230 (98.3)
Tocilizumab or sarilumab 173/228 (75.9) 165/217 (76.0) 183/230 (79.6)
Baricitinib 2/228 (0.9) 6/217 (2.8) 9/230 (3.9)
Antiviral monoclonal antibody 1/228 (0.4) 2/217 (0.9) 2/230 (0.9)
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Abbreviations: ACE, angiotensin-converting enzyme; APACHE, Acute Physiology and Chronic Health Evaluation; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; FiO2, fraction of inspired oxygen; Pao2, partial pressure of oxygen.

SI conversion: To convert creatinine to μmol/L, multiply by 88.4.

a

Due to the small sample size (n = 6), data on patients randomized to the ARB and DMX-200 group are not presented. Percentages may not sum to 100 because of rounding.

b

Data collection was not approved in Canada and continental Europe. “Other” includes responses of “declined” and “other ethnic group.” Participants (or their surrogates) self-reported their race and ethnicity via fixed categories appropriate to their region. “Declined” does not simply represent missing data; a patient may have declined to provide their race and ethnicity at the time of registration or the person performing the registration may decline to ask the patient to clarify race and ethnicity at the time of registration.

c

Measures illness severity based on age, medical history, and physiologic variables (range, 0-71; higher scores indicate increasing severity).

d

A global measure of fitness and frailty (range, 1 [very fit] to 9 [terminally ill]).

e

SARS-CoV2 infection was confirmed by respiratory tract polymerase chain reaction testing. Patients were eligible for enrollment if COVID-19 testing had been performed and results confirmed SARS-CoV-2 or if testing had not been performed but was intended to occur. After enrollment, SARS-CoV-2 was not confirmed in 8 patients, either due to negative test results or the absence of testing. These patients were included in the intention-to-treat analysis.

f

Kidney disease was determined from the most recent stable serum creatinine level prior to this hospital admission, except in patients who were receiving dialysis. Abnormal kidney function was defined as a creatinine level of 130 μmol/L (1.5 mg/dL) or greater for men or 100 μmol/L (1.1 mg/dL) or greater for women not previously receiving dialysis. Cardiovascular disease was defined as New York Heart Association class IV symptoms. Immunosuppression was defined by the receipt of recent chemotherapy, radiation, high-dose or long-term steroid treatment, or presence of immunosuppressive disease.

g

A normal Pao2/FiO2 ratio is ≥400.

h

The Extended Cardiovascular Sequential Organ Failure Assessment (SOFA) score reflects criteria for blood pressure and inotropic or vasoactive support, with higher scores indicating worse cardiovascular organ failure.

i

Laboratory results were available when captured for clinical care.

j

Within 48 hours of randomization.

Primary Outcome

Among 679 critically ill patients, the median (IQR) number of organ support–free days 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) (Figure 2), corresponding to adjusted ORs of 0.77 (95% CrI, 0.58-1.06) for ACE inhibitors and 0.76 (95% CrI, 0.56-1.05) for ARBs compared with control (Table 2). The posterior probabilities that treatment worsened organ support–free days compared with control were 94.9% for ACE inhibitors and 95.4% for ARBs. Results were generally consistent in sensitivity analyses, including after adjustment for potentially imbalanced baseline variables (eTable 5 in Supplement 2). There were no consistent, clinically relevant deviations from the assumption of proportional effects across the scale of organ support–free days (eFigure 2 in Supplement 2). Outcomes were available for only 6 critically ill patients randomized to the combined ARB and DMX-200 intervention (eFigure 3 in Supplement 2). Among 56 non–critically ill patients, the median (IQR) number of organ support–free days in all groups was 22 (22-22) (eFigure 4 in Supplement 2) and posterior probabilities were inconclusive (eTable 6 in Supplement 2).

Figure 2. Organ Support–Free Days Up to Day 21 in Critically Ill Patients.

Figure 2.

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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.

Table 2. Primary and Select Secondary Outcomes in Critically Ill Patientsa.

Outcome Median (IQR) ACE inhibitor vs control ARB vs control
Control (n = 231) ACE inhibitor (n = 231) ARB (n = 217) Adjusted odds ratio (95% CrI)b Probability of efficacyc Probability of harmc Adjusted odds ratio (95% CrI)d Probability of efficacyb Probability of harmb
Primary outcome
Organ support–free dayse,f 12 (0 to 17) 10 (−1 to 16) 8 (−1 to 17) 0.77 (0.58 to 1.06) 5.1 94.9 0.76 (0.56 to 1.05) 4.6 95.4
Secondary outcomes, No./total No. (%)
In-hospital survival 182/231 (78.8) 166/231 (71.9) 152/217 (70.0) 0.70 (0.44 to 1.06) 4.7 95.3 0.62 (0.39 to 0.98) 1.9 98.1
90-d survivalg 0.70 (0.49 to 1.02) 3.1 96.9 0.67 (0.46 to 0.96) 1.4 98.6
KDIGO AKI stage 2 or higher by day 14h 16/212 (7.5) 16/223 (7.2) 30/208 (14.4) 0.85 (0.43 to 1.69) 67.2 32.8 1.87 (1.02 to 3.48) 2.2 97.8
KDIGO AKI stage 3 by day 14i 12/212 (5.7) 12/223 (5.4) 23/208 (11.1) 0.87 (0.39 to 1.90) 64.2 35.8 1.78 (0.89 to 3.58) 5.4 94.6
Vasopressor-/inotrope-free daysd 28 (7.5 to 28) 26 (−1 to 28) 24 (−1 to 28) 0.75 (0.53 to 1.07) 6.0 94.0 0.62 (0.44 to 0.89) 0.4 99.7
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Abbreviations: ACE, angiotensin-converting enzyme; AKI, acute kidney injury; ARB, angiotensin receptor blocker; CrI, credible interval; KDIGO, Kidney Disease Improving Global Outcomes.

a

Additional secondary outcomes in critically ill patients are reported in eTable 7 in Supplement 2. Due to the low number of patients with available outcomes in the combined ARB and DMX-200 group (n = 6), effect estimates were not calculated in this group; rather, distributions of the primary outcome are shown in eFigure 1 in Supplement 2 and descriptive data on secondary outcomes are reported in footnotes in eTable 7 in Supplement 2.

b

Values are median odds ratios. Odds ratios for organ support–free days and in-hospital survival are adjusted for age, sex, site (nested within country), domain eligibility, randomization within each domain, and time epochs. Odds ratios for the remaining outcomes are adjusted for age and sex. Odds ratios >1 correspond with treatment benefit and <1 correspond with treatment harm, except in the reporting of occurrence of acute kidney injury, wherein the direction of treatment effect is reversed to be consistent with the outcome description.

c

The probabilities of efficacy and harm of ACE inhibitor or ARB relative to the control group were computed from the posterior distributions.

d

This composite outcome included mortality and, among survivors, the number of days alive without vasopressor use through day 28. Among critically ill patients in the ACE inhibitor, ARB, and control groups, 69/188 (36.7%), 86/188 (45.7%), and 69/203 (34.0%) patients, respectively, received new initiation of vasopressors (after not receiving them at enrollment) after randomization.

e

The primary outcome was organ support–free days, evaluated using an ordinal scale that combined in-hospital death and the number of days without cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. The conditional median (IQR) organ support–free days for patients who survived hospitalization was 15 (8-18) for the ACE inhibitor group; 15 (6-18) for the ARB group, and 15 (9-18) for the control group.

f

Dynamic borrowing of information on treatment effect from non–critically ill patients was permitted. Results from a sensitivity analysis assuming independent treatment effects between disease severity cohorts are provided in eTable 5 in Supplement 2.

g

Time-to-event outcome. The effect estimates are median hazard ratios. Hazard ratios greater than 1 indicate benefit and less than 1 indicate harm of ACE inhibitor or ARB relative to the control group. The No./total (%) of patients alive at 90 days in each group was164 of 231 (71.0%) in the ACE inhibitor group, 151 of 217 (69.6%) in the ARB group, and 179 of 231 (77.5%) in the control group.

h

AKI was defined using the modified Kidney Disease Improving Global Outcomes (KDIGO) criteria as either stage 2 or higher (serum creatinine increase by 2-2.9 times from baseline, with baseline defined as time of enrollment) or as stage 3 (serum creatinine increase by ≥3 times from baseline, increase in serum creatinine by ≥0.5 mg/dL [44 mmol/L] to ≥4 mg/dL [353.6 μmol/L], or new initiation of kidney replacement therapy). An odds ratio <1 indicates treatment benefit, whereas an odds ratio >1 indicates treatment harm.

i

Need for kidney replacement therapy among patients meeting criteria for KDIGO stage 3 AKI by day 14: 4 of 223 (1.8%) in the ACE inhibitor group, 10 of 208 (4.8%) in the ARB group, and 4 of 212 (1.9%) in the control group. The occurrence of incident AKI at 7 days is reported in eTable 7 in Supplement 2.

Secondary Outcomes

None of the 15 secondary outcomes were improved with ACE inhibitor or ARB treatment compared with control (Table 2 and eTables 6, 7, and 8 in Supplement 2). Among critically ill patients, hospital survival occurred in 166 of 231 patients (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, corresponding to adjusted ORs of 0.70 (95% CrI, 0.44-1.06) for ACE inhibitors and 0.62 (95% CrI, 0.39-0.98) for ARBs compared with control. The posterior probabilities that ACE inhibitor and ARB initiation worsened hospital survival, compared with control, were 95.3% and 98.1%, respectively. The probability was high that ACE inhibitor and ARB initiation reduced survival through 90 days (Figure 3). Among non–critically ill patients, 1 death occurred (in the ACE inhibitor group).

Figure 3. Survival Through 90 Days in Critically Ill Patients and Treatment Effects on Hospital Survival.

Figure 3.

Open in a new tab

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.

Among critically ill patients, vasopressor therapy was newly initiated in 69 of 188 patients (36.7%) in the ACE inhibitor group, 86 of 188 (45.7%) in the ARB group, and 69 of 203 (34.0%) in the control group. The posterior probabilities that vasopressor-free days, a composite of death and vasopressor receipt, was worsened with ACE inhibitor initiation was 94.0% and ARB initiation of 99.7%. Median (IQR) ratio of peak to baseline creatinine was 1.11 (1.00-1.25) in the ACE inhibitor group, 1.15 (1.00-1.42) in the ARB group, and 1.11 (1.00-1.30) in the control group (eFigure 5 in Supplement 2). The occurrence of Kidney Disease Improving Global Outcomes stage 2 or higher AKI within 14 days following randomization was 7.2% in the ACE inhibitor group, 14.4% in the ARB group, and 7.5% in the control group. Among non–critically ill patients, vasopressor receipt and AKI were infrequent (eTables 6 and 8 in Supplement 2). Evaluation of secondary outcomes in the combined ARB and DMX-200 group was limited by low enrollment.

Among critically ill patients, serious adverse events were reported in 2 of 232 patients (0.9%) in the ACE inhibitor group, 5 of 218 (2.3%) in the ARB group, 0 of 6 (0.0%) in the combined DMX-200 and ARB group, and 4 of 231 (1.7%) in the control group; there was 1 serious adverse event among non–critically ill patients (in the ACE inhibitor group; eTable 9 in Supplement 2).

Subgroup Analyses

In subgroup analyses, treatment effects among critically ill patients did not meaningfully vary by age, sex, mechanical ventilation receipt, or baseline estimated glomerular filtration rate (eFigures 6 and 7 in Supplement 2). Among patients receiving vasopressors at enrollment, the OR for organ support–free days with an ACE inhibitor compared with control was 0.54 (95% CrI, 0.30-0.97) vs 0.90 (95% CrI, 0.66-1.25) among patients not receiving vasopressors. ARB treatment effect did not differ by baseline vasopressor receipt. In causal forest analyses considering whether there was evidence of heterogeneous treatment effects across all available baseline variables (eTable 10 in Supplement 2), subgroup conditional average treatment effects were similar for ACE inhibitor and ARB use (eFigure 8 in Supplement 2). No subgroup showed strong evidence of heterogeneity (eFigure 8 in Supplement 2). Point estimates of expected conditional average treatment effects at the individual level consistently favored worsened hospital survival for both treatments vs control, but with 95% CIs that included null for the majority (>70%) of patients (Figure 3).

Discussion

In this domain of an overarching platform trial, among critically ill patients hospitalized for COVID-19, there was a 95% probability that ACE inhibitor or ARB initiation worsened organ support–free days, primarily due to differences in hospital survival. The domain was terminated due to safety concerns, and findings are inconclusive for non–critically ill patients and those in the combined ARB and DMX-200 treatment group.

RAS activation may contribute to poor clinical outcomes in patients with acute hypoxemic respiratory failure,30,31,32,33,34 including COVID-19.3,8,35,36,37 Angiotensin II is upregulated in COVID-19 and other severe respiratory infections, proportional to severity.38,39 Inhibition of angiotensin II with ACE inhibitors or ARBs improves respiratory and other organ failure in animal models of SARS-CoV-2 infection,12 SARS-CoV-1 infection,7 sepsis,40,41,42,43,44,45 aspiration,15 and ventilator-induced lung injury.42,46,47,48,49,50,51,52 Observational studies suggest more favorable outcomes among existing users of ACE inhibitors and ARBs who develop COVID-19 and other respiratory infections compared with nonusers.11,13,14,53,54,55 However, animal models inconsistently correlate with human host response56 and observational studies are at risk for bias.57

Analyses suggest that there was a high probability that inhibiting angiotensin II, either by reducing its production (ACE inhibitors) or blocking its effect (ARBs), worsened outcomes among critically ill patients. In prespecified subgroup and causal forest heterogeneity of treatment effect analyses, there was no evidence that any subgroup benefited based on these analyses. Although a trend toward lower hospital survival was observed with treatment for some higher-risk subgroups, there was no clear evidence of differential effect by baseline characteristics to support a mechanistic hypothesis. Among secondary outcomes, vasopressor receipt and AKI were more frequent with ARB initiation, although less clearly so with ACE inhibitor initiation.

In an early pandemic trial of 162 hospitalized patients with COVID-19 excluding those admitted to an ICU, telmisartan improved survival and reduced inflammatory biomarkers compared with control58; however, enrollment was prematurely terminated, limiting inference. In a 2022 trial of 205 patients, oxygenation and survival were not improved with losartan compared with placebo, although hypotension and AKI occurred more frequently with losartan.59 A 2022 meta-analysis of smaller and incomplete trials observed no survival benefit with RAS inhibitor initiation for COVID-19, and hypotension and AKI appeared more frequent in severely ill patients.60 The CLARITY trial, which included lower-risk patients, did not observe a benefit of telmisartan initiation in hospitalized patients with COVID-19.61 The current trial included the highest proportion of critically ill patients, who are at greatest risk of hypotension and AKI, which may explain the more evident harm signal. Importantly, previous randomized clinical trials evaluating continuation compared with discontinuation of RAS inhibitors in less severely ill patients hospitalized for COVID-19 suggest their continuation is safe,62 although there is uncertainty among more severely ill patients.63,64

Strengths of this trial include its pragmatic evaluation of candidate repurposed, widely-available treatments in diverse international settings. Consistency of treatment effects across both ACE inhibitor and ARB initiation supports inference across shared mechanisms of action. The application of a 2-stage design with graduation rules permitted efficient evaluation of early candidate treatments. Finally, the application of forest-based techniques suited to high-dimensional data permitted a broad evaluation of potentially clinically important effect modifiers and may overcome some of the limitations of conventional subgroup analyses.

Limitations

This trial has several limitations. First, the protocol was pragmatic and agents and dose equivalents varied; nevertheless, 89% of patients in each group received the same agent and dose equivalents were consistently low to moderate. Second, approximately 1 in 20 randomized patients withdrew consent and were excluded from this analysis. However, the frequency was similar across groups and similar to other acute care trials in which patients often lack capacity to provide consent at the time of enrollment. Third, some potentially relevant baseline characteristics (eg, vasopressor receipt) were imbalanced; these imbalances may have had a modest influence on treatment effect estimates. Fourth, this trial evaluated new RAS antagonist initiation specifically as treatment for COVID-19 and not the separate question of whether to continue or discontinue existing therapy. Fifth, the trial was terminated for safety concerns after enrollment of only a modest sample size. Although this may leave uncertainty about precise treatment effects, the likelihood of meaningful clinical benefit is low. Sixth, due to being available later and offered only at a subset of sites, enrollment in the combined ARB and DMX-200 group was low at the time of closure of enrollment.

Conclusions

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.

Section Editor: Christopher Seymour, MD, Associate Editor, JAMA (christopher.seymour@jamanetwork.org).

Supplement 1.

Trial Protocol and SAP Documents

jama-e234480-s001.pdf (6.4MB, pdf)
Supplement 2.

The REMAP-CAP Investigators

eAppendix 1. Supplementary Methods

eAppendix 2. Supplementary Results

eTable 1. Study Drug Intensity Dose Equivalents for Retrospective Categorization

eTable 2. Noncritically Ill Participant Characteristics at Baseline

eTable 3. Study Drug Intensity Dose Equivalents

eTable 4. Reasons for Discontinuation of Treatment

eTable 5. Sensitivity Analyses of the Primary Outcome and In-Hospital Survival Using Different Analytical Populations – Critically Ill Patients

eTable 6. Primary Outcome (Organ Support-Free Days) and Key Secondary Outcomes in the Non-critically Ill Population

eTable 7. Other Secondary Outcomes in the Critically Ill Population

eTable 8. Sensitivity Analyses of the Primary Outcome and Secondary Outcomes in the Non-critically Ill Population

eTable 9. Serious Adverse Events

eTable 10. Baseline Covariates among Critically Ill and Noncritically Ill Patients Used for Causal Forests Analysis

eFigure 1. Schematic of 2-Stage Design Employed by This Domain

eFigure 2. Evaluation of Proportional Effects Assumption among Critically Ill Patients

eFigure 3. Distribution of the Primary Outcome in the Combined ARB and DMX-200

Intervention Group among Critically Ill Patients

eFigure 4. Distribution of the Primary Outcome among Noncritically Ill Patients

eFigure 5. Relative Change in Baseline to Peak Creatinine among Critically Ill Patients

eFigure 6. ACE inhibitor and ARB Subgroup Analyses Using a Bayesian Cumulative

Logistic Model for Organ Support-Free Days

eFigure 7. ACE inhibitor and ARB Subgroup Analyses Using a Bayesian Cumulative

Logistic Model for Hospital Survival

eFigure 8. ACE inhibitor, ARB, and Pooled Causal Forest Subgroup Effects on Hospital Survival

jama-e234480-s002.pdf (2.3MB, pdf)
Supplement 3.

Nonauthor collaborators

jama-e234480-s003.pdf (1,021.4KB, pdf)
Supplement 4.

Data sharing statement

jama-e234480-s004.pdf (22.2KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol and SAP Documents

jama-e234480-s001.pdf (6.4MB, pdf)
Supplement 2.

The REMAP-CAP Investigators

eAppendix 1. Supplementary Methods

eAppendix 2. Supplementary Results

eTable 1. Study Drug Intensity Dose Equivalents for Retrospective Categorization

eTable 2. Noncritically Ill Participant Characteristics at Baseline

eTable 3. Study Drug Intensity Dose Equivalents

eTable 4. Reasons for Discontinuation of Treatment

eTable 5. Sensitivity Analyses of the Primary Outcome and In-Hospital Survival Using Different Analytical Populations – Critically Ill Patients

eTable 6. Primary Outcome (Organ Support-Free Days) and Key Secondary Outcomes in the Non-critically Ill Population

eTable 7. Other Secondary Outcomes in the Critically Ill Population

eTable 8. Sensitivity Analyses of the Primary Outcome and Secondary Outcomes in the Non-critically Ill Population

eTable 9. Serious Adverse Events

eTable 10. Baseline Covariates among Critically Ill and Noncritically Ill Patients Used for Causal Forests Analysis

eFigure 1. Schematic of 2-Stage Design Employed by This Domain

eFigure 2. Evaluation of Proportional Effects Assumption among Critically Ill Patients

eFigure 3. Distribution of the Primary Outcome in the Combined ARB and DMX-200

Intervention Group among Critically Ill Patients

eFigure 4. Distribution of the Primary Outcome among Noncritically Ill Patients

eFigure 5. Relative Change in Baseline to Peak Creatinine among Critically Ill Patients

eFigure 6. ACE inhibitor and ARB Subgroup Analyses Using a Bayesian Cumulative

Logistic Model for Organ Support-Free Days

eFigure 7. ACE inhibitor and ARB Subgroup Analyses Using a Bayesian Cumulative

Logistic Model for Hospital Survival

eFigure 8. ACE inhibitor, ARB, and Pooled Causal Forest Subgroup Effects on Hospital Survival

jama-e234480-s002.pdf (2.3MB, pdf)
Supplement 3.

Nonauthor collaborators

jama-e234480-s003.pdf (1,021.4KB, pdf)
Supplement 4.

Data sharing statement

jama-e234480-s004.pdf (22.2KB, pdf)

Articles from JAMA are provided here courtesy of American Medical Association

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