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Randomized Controlled Trial
. 2020 Oct;22(10):1780-1788.
doi: 10.1111/jch.14011. Epub 2020 Sep 16.

Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol

Jordana B Cohen  1   2 , Thomas C Hanff  2   3 , Vicente Corrales-Medina  4 , Preethi William  5 , Nicolas Renna  6 , Nelson R Rosado-Santander  7 , Juan E Rodriguez-Mori  8 , Jonas Spaak  9 , Jaime Andrade-Villanueva  10 , Tara I Chang  11 , Alejandro Barbagelata  12   13 , Carlos E Alfonso  14 , Eduardo Bernales-Salas  7 , Johanna Coacalla  7 , Carlos Augusto Castro-Callirgos  8 , Karen E Tupayachi-Venero  8 , Carola Medina  15 , Renzo Valdivia  15 , Mirko Villavicencio  15 , Charles R Vasquez  2   16 , Michael O Harhay  2   17 , Jesse Chittams  2 , Tiffany Sharkoski  3 , James Brian Byrd  18 , Daniel L Edmonston  19 , Nancy Sweitzer  5 , Julio A Chirinos  3
Affiliations
Randomized Controlled Trial

Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol

Jordana B Cohen et al. J Clin Hypertens (Greenwich). 2020 Oct.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin-converting enzyme 2 (ACE2), which facilitates SARS-CoV-2 host cell entry, may be impacted by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long-term outpatient ACEI or ARB upon hospitalization with COVID-19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project.

Keywords: COVID-19; angiotensin receptor blocker; angiotensin-converting enzyme inhibitor; angiotensin-converting enzyme inhibitor 2; clinical trial; coronavirus; hypertension.

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Conflict of interest statement

In the last 2 years, JAC has received consulting honoraria from Sanifit, Bristol Myers Squibb, Edwards Lifesciences, Bayer, and JNJ and research grants from the National Institutes of Health, Microsoft, Fukuda‐Denshi, and Bristol Myers Squibb. He has received compensation from the American Heart Association and the American College of Cardiology for editorial roles, and visiting speaker honoraria from Washington University and University of Utah. JS has received speaker honoraria and is on the advisory boards for AstraZeneca, Vifor Pharma, and Novo Nordisk, and has received speaker honoraria from AMGEN. JBB has received research grants from Fast Grants for this study, as well as from the National Institutes of Health. TIC has received funding paid by Janssen Pharmaceuticals to Stanford University; has served as a consultant for Bayer, Janssen Pharmaceuticals, Novo Nordisk, Fresenius Medical Care, Tricida, Gilead, and AstraZeneca; and has received grant support from Satellite Healthcare, the American Heart Association, and the National Institutes of Health.

Figures

Figure 1
Figure 1
The counterregulatory role of ACE2 in the renin‐angiotensin system. Angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers may increase ACE2 levels. This effect is speculated to increase the risk of SARS‐CoV‐2 host cell entry but may also have important anti‐inflammatory effects
Figure 2
Figure 2
Study overview and design
Figure 3
Figure 3
Geographic distribution of study sites enrolling participants in the REPLACE COVID trial. As of August 10, 2020, 136 participants have been enrolled across sites in the United States, Canada, Mexico, Peru, Argentina, Bolivia, and Sweden. Additional sites in the United States and Brazil are initiating enrollment
Figure 4
Figure 4
The REPLACE COVID global rank score. Participants are ranked from worst to best outcomes by (1) days in hospital to death; (2) days on invasive mechanical ventilation or extracorporeal membrane oxygenation; (3) days on renal replacement therapy or inotropic/vasopressor therapy; and (4) area under the curve of a modified SOFA score
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