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Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19A Randomized Clinical Trial

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To identify the key insights or developments described in this article
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Key Points

Question  Does discontinuation compared with continuation of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) change the number of days alive and out of the hospital through 30 days in patients hospitalized with mild to moderate coronavirus disease 2019 (COVID-19)?

Findings  In this randomized clinical trial that included 659 patients hospitalized with mild to moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, the mean number of days alive and out of the hospital for those assigned to discontinue vs continue these medications was 21.9 vs 22.9, respectively, a difference that was not statistically significant.

Meaning  These findings do not support routinely discontinuing ACEIs or ARBs among patients hospitalized with mild to moderate COVID-19.

Abstract

Importance  It is unknown whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have a positive, neutral, or negative effect on clinical outcomes in patients with coronavirus disease 2019 (COVID-19).

Objective  To determine whether discontinuation compared with continuation of ACEIs or ARBs changed the number of days alive and out of the hospital through 30 days.

Design, Setting, and Participants  A randomized clinical trial of 659 patients hospitalized in Brazil with mild to moderate COVID-19 who were taking ACEIs or ARBs prior to hospitalization (enrolled: April 9-June 26, 2020; final follow-up: July 26, 2020).

Interventions  Discontinuation (n = 334) or continuation (n = 325) of ACEIs or ARBs.

Main Outcomes and Measures  The primary outcome was the number of days alive and out of the hospital through 30 days. Secondary outcomes included death, cardiovascular death, and COVID-19 progression.

Results  Among 659 patients, the median age was 55.1 years (interquartile range [IQR], 46.1-65.0 years), 14.7% were aged 70 years or older, 40.4% were women, and 100% completed the trial. The median time from symptom onset to hospital admission was 6 days (IQR, 4-9 days) and 27.2% of patients had an oxygen saturation of less than 94% of room air at baseline. In terms of clinical severity, 57.1% of patients were considered mild at hospital admission and 42.9% were considered moderate. There was no significant difference in the number of days alive and out of the hospital in patients in the discontinuation group (mean, 21.9 days [SD, 8 days]) vs patients in the continuation group (mean, 22.9 days [SD, 7.1 days]) and the mean ratio was 0.95 (95% CI, 0.90-1.01). There also was no statistically significant difference in death (2.7% for the discontinuation group vs 2.8% for the continuation group; odds ratio [OR], 0.97 [95% CI, 0.38-2.52]), cardiovascular death (0.6% vs 0.3%, respectively; OR, 1.95 [95% CI, 0.19-42.12]), or COVID-19 progression (38.3% vs 32.3%; OR, 1.30 [95% CI, 0.95-1.80]). The most common adverse events were respiratory failure requiring invasive mechanical ventilation (9.6% in the discontinuation group vs 7.7% in the continuation group), shock requiring vasopressors (8.4% vs 7.1%, respectively), acute myocardial infarction (7.5% vs 4.6%), new or worsening heart failure (4.2% vs 4.9%), and acute kidney failure requiring hemodialysis (3.3% vs 2.8%).

Conclusions and Relevance  Among patients hospitalized with mild to moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, there was no significant difference in the mean number of days alive and out of the hospital for those assigned to discontinue vs continue these medications. These findings do not support routinely discontinuing ACEIs or ARBs among patients hospitalized with mild to moderate COVID-19 if there is an indication for treatment.

Trial Registration  ClinicalTrials.gov Identifier: NCT04364893

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Article Information

Corresponding Author: Renato D. Lopes, MD, PhD, Duke Clinical Research Institute, 200 Morris St, Durham, NC 27701 (renato.lopes@dm.duke.edu).

Accepted for Publication: December 13, 2020.

Author Contributions: Dr Lopes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lopes, Macedo, de Barros E Silva, Moll-Bernardes, Mazza, Feldman, D’Andrea Saba Arruda, de Albuquerque, de Sousa, Dionísio, Granger, Alexander, de Souza.

Acquisition, analysis, or interpretation of data: Lopes, Macedo, de Barros E Silva, Moll-Bernardes, dos Santos, Feldman, D’Andrea Saba Arruda, Camiletti, de Paula, Giusti, Domiciano, Noya-Rabelo, Hamilton, Loures, Dionísio, Furquim, De Luca, dos Santos Sousa, Bandeira, Zukowski, de Oliveira, Ribeiro, de Moraes, Petriz, Pimentel, Miranda, de Jesus Abufaiad, Gibson, Alexander.

Drafting of the manuscript: Lopes, Macedo, de Barros E Silva, Moll-Bernardes, Feldman, D’Andrea Saba Arruda, de Albuquerque, Camiletti, de Sousa, Dionísio, Zukowski, de Moraes, Miranda.

Critical revision of the manuscript for important intellectual content: Lopes, Macedo, de Barros E Silva, Moll-Bernardes, dos Santos, Mazza, Feldman, D’Andrea Saba Arruda, de Sousa, de Paula, Giusti, Domiciano, Noya-Rabelo, Hamilton, Loures, Dionísio, Furquim, De Luca, dos Santos Sousa, Bandeira, de Oliveira, Ribeiro, Petriz, Pimentel, de Jesus Abufaiad, Gibson, Granger, Alexander, de Souza.

Statistical analysis: Macedo, dos Santos, D’Andrea Saba Arruda, de Paula.

Obtained funding: Lopes, Moll-Bernardes.

Administrative, technical, or material support: Lopes, Macedo, Moll-Bernardes, Mazza, Feldman, D’Andrea Saba Arruda, de Albuquerque, Camiletti, de Sousa, de Paula, Giusti, Domiciano, Noya-Rabelo, Loures, Dionísio, Furquim, De Luca, Bandeira, de Oliveira, de Moraes, de Jesus Abufaiad, de Souza.

Supervision: Lopes, Macedo, de Barros E Silva, Moll-Bernardes, Feldman, D’Andrea Saba Arruda, de Albuquerque, Camiletti, de Sousa, Giusti, Noya-Rabelo, Dionísio, Petriz, Pimentel, Miranda, de Jesus Abufaiad.

Conflict of Interest Disclosures: Dr Lopes reported receiving grant support from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Sanofi, and Pfizer; and receiving consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Sanofi, and Portola. Dr Macedo reported receiving consulting fees from Pfizer, Bayer, AstraZeneca, Novartis, Daiichi-Sankyo, Zodiac, Roche, and Janssen. Dr de Barros E Silva reported receiving grants from Pfizer, Bayer, and Roche Diagnostics; and receiving consulting fees from Pfizer, Bayer, and Roche Diagnostics. Dr Feldman reported receiving consulting fees from Pfizer, Bayer, Daiichi-Sankyo, Boehringer, and Servier. Dr D’Andrea Saba Arruda reported receiving consulting fees from Bayer, Pfizer, Servier, AstraZeneca, and Daichii Sankyo. Dr de Albuquerque reported receiving consulting fees from Boehringer Ingelheim, AstraZeneca, Bayer, and Servier. Dr de Oliveira reported receiving consulting fees from Bayer, Boehringer-Ingelheim, Servier, and Novartis. Dr Petriz reported receiving consulting fees from Bayer, Pfizer, and Daichii Sankyo. Dr Gibson reported receiving consulting fees and grants from Johnson & Johnson, Janssen, and Bayer. Dr Granger reported receiving grant support from AstraZeneca, the US Food and Drug Administration, the National Institutes of Health, GlaxoSmithKline, Medtronic, Novartis, Apple, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Janssen; receiving consulting fees from AstraZeneca, Espero, GlaxoSmithKline, Medtronic, Novartis, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Merck, Roche, Eli Lilly, and Janssen; and that all relationships with industry are listed at dcri.org/about-us/conflict-of-interest/. Dr Alexander reported receiving grant support from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, CryoLife, CSL Behring, GlaxoSmithKline, Ferring, the US Food and Drug Administration, the National Institutes of Health, and XaTek; and receiving consulting fees from AbbVie, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, CryoLife, CSL Behring, Novo Nordisk, Pfizer, Portola, Quantum Genomics, the US Department of Veterans Affairs, XaTek, Inositec, and Zafgen. Dr de Souza reported receiving grant support from Boehringer Ingelheim; and receiving consulting fees from Pfizer, Bayer, Daiichi-Sankyo, and Boehringer Ingelheim. No other disclosures were reported.

The BRACE CORONA Principal Investigators: The BRACE CORONA Principal Investigators are listed in Supplement 2.

Data Sharing Statement: See Supplement 4.

Additional Information: The trial was designed and led by an academic executive committee whose members were responsible for the trial’s conduct. Only authors contributed to the writing of the article. The executive committee members are listed in Supplement 2.

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