RAAS inhibitors are not associated with mortality in COVID-19 patients: Findings from an observational multicenter study in Italy and a meta-analysis of 19 studies

COVID-19 RISk and Treatments (CORIST) Collaboration, Augusto Di Castelnuovo, Simona Costanzo, Andrea Antinori, Nausicaa Berselli, Lorenzo Blandi, Marialaura Bonaccio, Roberto Cauda, Alessandro Gialluisi, Giovanni Guaraldi, Lorenzo Menicanti, Marco Mennuni, Roberta Mussinelli, Ilaria My, Giustino Parruti, Giuseppe Patti, Stefano Perlini, Francesca Santilli, Carlo Signorelli, Giulio G Stefanini, Alessandra Vergori, Pasquale Abete, Walter Ageno, Piergiuseppe Agostoni, Luca Aiello, Samir Al Moghazi, Rosa Arboretti, Filippo Aucella, Greta Barbieri, Martina Barchitta, Alessandro Bartoloni, Paolo Bonfanti, Francesco Cacciatore, Lucia Caiano, Laura Carrozzi, Antonio Cascio, Giacomo Castiglione, Stefania Cianfrone, Arturo Ciccullo, Antonella Cingolani, Francesco Cipollone, Claudia Colomba, Crizia Colombo, Ottavia Cozzi, Annalisa Crisetti, Francesca Crosta, Gian Battista Danzi, Damiano D'Ardes, Katleen de Gaetano Donati, Francesco Di Gennaro, Giuseppe Di Tano, Gianpiero D'Offizi, Francesco Maria Fusco, Ivan Gentile, Emauele Graziani, Gabriella Guarnieri, Giovanni Larizza, Armando Leone, Veronica Lio, Mothanje Barbara Lucia, Gloria Maccagni, Ferruccio Madaro, Stefano Maitan, Sandro Mancarella, Rosa Manuele, Massimo Mapelli, Riccardo Maragna, Rossella Marcucci, Giulio Maresca, Silvia Marongiu, Claudia Marotta, Lorenzo Marra, Franco Mastroianni, Maria Mazzitelli, Alessandro Mengozzi, Francesco Menichetti, Marianna Meschiari, Jovana Milic, Filippo Minutolo, Beatrice Molena, Cristina Mussini, Maria Musso, Anna Odone, Marco Olivieri, Antonella Palimodde, Emanuela Pasi, Raffaele Pesavento, Francesco Petri, Biagio Pinchera, Carlo A Pivato, Venerino Poletti, Claudia Ravaglia, Marco Rossato, Marianna Rossi, Anna Sabena, Francesco Salinaro, Vincenzo Sangiovanni, Carlo Sanrocco, Giancarlo Scoppettuolo, Laura Scorzolini, Raffaella Sgariglia, Paola Giustina Simeone, Enrico Maria Trecarichi, Roberto Vettor, Andrea Vianello, Marco Vinceti, Alexandra Virano, Laura Vocciante, Raffaele De Caterina, Licia Iacoviello, COVID-19 RISk and Treatments (CORIST) Collaboration, Augusto Di Castelnuovo, Simona Costanzo, Andrea Antinori, Nausicaa Berselli, Lorenzo Blandi, Marialaura Bonaccio, Roberto Cauda, Alessandro Gialluisi, Giovanni Guaraldi, Lorenzo Menicanti, Marco Mennuni, Roberta Mussinelli, Ilaria My, Giustino Parruti, Giuseppe Patti, Stefano Perlini, Francesca Santilli, Carlo Signorelli, Giulio G Stefanini, Alessandra Vergori, Pasquale Abete, Walter Ageno, Piergiuseppe Agostoni, Luca Aiello, Samir Al Moghazi, Rosa Arboretti, Filippo Aucella, Greta Barbieri, Martina Barchitta, Alessandro Bartoloni, Paolo Bonfanti, Francesco Cacciatore, Lucia Caiano, Laura Carrozzi, Antonio Cascio, Giacomo Castiglione, Stefania Cianfrone, Arturo Ciccullo, Antonella Cingolani, Francesco Cipollone, Claudia Colomba, Crizia Colombo, Ottavia Cozzi, Annalisa Crisetti, Francesca Crosta, Gian Battista Danzi, Damiano D'Ardes, Katleen de Gaetano Donati, Francesco Di Gennaro, Giuseppe Di Tano, Gianpiero D'Offizi, Francesco Maria Fusco, Ivan Gentile, Emauele Graziani, Gabriella Guarnieri, Giovanni Larizza, Armando Leone, Veronica Lio, Mothanje Barbara Lucia, Gloria Maccagni, Ferruccio Madaro, Stefano Maitan, Sandro Mancarella, Rosa Manuele, Massimo Mapelli, Riccardo Maragna, Rossella Marcucci, Giulio Maresca, Silvia Marongiu, Claudia Marotta, Lorenzo Marra, Franco Mastroianni, Maria Mazzitelli, Alessandro Mengozzi, Francesco Menichetti, Marianna Meschiari, Jovana Milic, Filippo Minutolo, Beatrice Molena, Cristina Mussini, Maria Musso, Anna Odone, Marco Olivieri, Antonella Palimodde, Emanuela Pasi, Raffaele Pesavento, Francesco Petri, Biagio Pinchera, Carlo A Pivato, Venerino Poletti, Claudia Ravaglia, Marco Rossato, Marianna Rossi, Anna Sabena, Francesco Salinaro, Vincenzo Sangiovanni, Carlo Sanrocco, Giancarlo Scoppettuolo, Laura Scorzolini, Raffaella Sgariglia, Paola Giustina Simeone, Enrico Maria Trecarichi, Roberto Vettor, Andrea Vianello, Marco Vinceti, Alexandra Virano, Laura Vocciante, Raffaele De Caterina, Licia Iacoviello

Abstract

Objective: The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID-19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418) to retrospectively investigate the relationship between RAAS inhibitors and COVID-19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies.

Methods: We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method.

Results: Out of 4069 COVID-19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID-19 treatments: 0.96, 95% confidence interval 0.77-1.20 and HR = 0.89, 0.67-1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78-1.26 and HR = 0.88, 0.65-1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID-19 adult patients, 9700 with hypertension) confirmed the absence of association.

Conclusions: In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID-19 patients.

Keywords: ACE-I; ARB; Angiotensin converting enzyme inhibitors; Angiotensin receptor blockers; COVID−19; Mortality; Sartans.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Forest plot for association of ACE-I or ARB with COVID-19 severity and/or mortality in all patients (panel A) or in patients with hypertension (panel B).

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