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

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. © 2023 American Medical Association. All rights reserved.

Importancia: La sobreactivación del sistema renina-angiotensina (RAS) puede contribuir a malos resultados clínicos en pacientes con COVID-19. Objetivo: Determinar si el inicio del inhibidor de la enzima convertidora de angiotensina (ECA) o del bloqueador de los receptores de angiotensina (BRA) mejora los resultados en pacientes hospitalizados por COVID-19. DISEÑO, AMBIENTE Y PARTICIPANTES: En un ensayo clínico aleatorizado de plataforma adaptativa en curso, 721 adultos hospitalizados en estado crítico y 58 no críticos fueron aleatorizados para recibir un inhibidor de RAS o un control entre el 16 de marzo de 2021 y el 25 de febrero de 2022, en 69 sitios en 7 países (seguimiento final el 1 de junio de 2022). INTERVENCIONES: Los pacientes fueron aleatorizados para recibir inicio abierto de un inhibidor de la ECA (n = 257), BRA (n = 248), BRA en combinación con DMX-200 (un inhibidor del receptor de quimiocinas 2; n = 10), o ningún Inhibidor de RAS (control; n = 264) por hasta 10 días. PRINCIPALES RESULTADOS Y MEDIDAS: El resultado primario fueron los días sin soporte de órganos, una combinación de supervivencia hospitalaria y días de vida sin soporte de órganos cardiovascular o respiratorio durante 21 días. El análisis principal fue un modelo logístico acumulativo bayesiano. Los odds ratios (OR) superiores a 1 representan mejores resultados. RESULTADOS: El 25 de febrero de 2022, se suspendió la inscripción debido a problemas de seguridad. Entre 679 pacientes en estado crítico con datos de resultados primarios disponibles, la edad media fue de 56 años y 239 participantes (35,2%) eran mujeres. La mediana (RIQ) de días sin soporte de órganos entre pacientes en estado crítico fue de 10 (-1 a 16) en el grupo de inhibidores de la ECA (n = 231), 8 (-1 a 17) en el grupo de BRA (n = 217) y 12 (0 a 17) en el grupo de control (n = 231) (odds ratio ajustado mediano de 0,77 [intervalo de credibilidad bayesiano del 95%, 0,58-1,06] para la mejora con el inhibidor de la ECA y 0,76 [intervalo de credibilidad del 95%, 0,56-1,05] para ARB en comparación con el control).}