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-Medina⁴, Preethi William⁵, Nicolas Renna⁶, Nelson R Rosado-Santander⁷, Juan E Rodriguez-Mori⁸, Jonas Spaak⁹, Jaime Andrade-Villanueva¹⁰, Tara I Chang¹¹, Alejandro Barbagelata^{12

13}, Carlos E Alfonso¹⁴, Eduardo Bernales-Salas⁷, Johanna Coacalla⁷, Carlos Augusto Castro-Callirgos⁸, Karen E Tupayachi-Venero⁸, Carola Medina¹⁵, Renzo Valdivia¹⁵, Mirko Villavicencio¹⁵, Charles R Vasquez^{2

16}, Michael O Harhay^{2

17}, Jesse Chittams², Tiffany Sharkoski³, James Brian Byrd¹⁸, Daniel L Edmonston¹⁹, Nancy Sweitzer⁵, Julio A Chirinos³

Affiliations

¹ Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Division of Infectious Diseases, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada.
⁵ Division of Cardiology, University of Arizona, Tucson, AZ, USA.
⁶ Hypertension Unit, Department of Pathology, Hospital Español de Mendoza, National University of Cuyo, IMBECU-CONICET, Mendoza, Argentina.
⁷ Department of Medicine, Hospital Nacional Carlos Alberto Seguín Escobedo, EsSalud, Arequipa, Perú.
⁸ Department of Nephrology, Hospital Nacional Alberto Sabogal Sologuren, EsSalud, Lima, Perú.
⁹ Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Universidad de Guadalajara, Guadalajara, Mexico.
¹¹ Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA.
¹² Universidad Católica de Buenos Aires, Buenos Aires, Argentina.
¹³ Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
¹⁴ Cardiology Division, University of Miami Miller School of Medicine, Miami, FL, USA.
¹⁵ Department of Nephrology, Hospital Nacional Edgardo Rebagliati Martins, EsSalud, Lima, Perú.
¹⁶ Department of Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Palliative and Advanced Illness Research (PAIR) Center and Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁸ Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
¹⁹ Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.

PMID: 32937008
PMCID: PMC7722152
DOI: 10.1111/jch.14011

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.

. 2020 Oct;22(10):1780-1788.

doi: 10.1111/jch.14011. Epub 2020 Sep 16.

Authors

Affiliations

¹ Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Division of Infectious Diseases, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada.
⁵ Division of Cardiology, University of Arizona, Tucson, AZ, USA.
⁶ Hypertension Unit, Department of Pathology, Hospital Español de Mendoza, National University of Cuyo, IMBECU-CONICET, Mendoza, Argentina.
⁷ Department of Medicine, Hospital Nacional Carlos Alberto Seguín Escobedo, EsSalud, Arequipa, Perú.
⁸ Department of Nephrology, Hospital Nacional Alberto Sabogal Sologuren, EsSalud, Lima, Perú.
⁹ Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Universidad de Guadalajara, Guadalajara, Mexico.
¹¹ Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA.
¹² Universidad Católica de Buenos Aires, Buenos Aires, Argentina.
¹³ Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
¹⁴ Cardiology Division, University of Miami Miller School of Medicine, Miami, FL, USA.
¹⁵ Department of Nephrology, Hospital Nacional Edgardo Rebagliati Martins, EsSalud, Lima, Perú.
¹⁶ Department of Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Palliative and Advanced Illness Research (PAIR) Center and Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁸ Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
¹⁹ Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.

PMID: 32937008
PMCID: PMC7722152
DOI: 10.1111/jch.14011

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**
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 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**
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

See this image and copyright information in PMC

References

1. Dong E, Du H, Gardner L. An interactive web‐based dashboard to track COVID‐19 in real time. Lancet Infect Dis. 2020;20(5):533‐534. - PMC - PubMed
1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID‐19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for disease control and prevention. JAMA. 2020;323(13):1239. - PubMed
1. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020;369:m1966. - PMC - PubMed
1. Sparks MA, Hiremath S, South A, et al. "The Coronavirus Conundrum: ACE2 and Hypertension Edition” NephJC. http://www.nephjc.com/news/covidace2. Accessed April 13, 2020.
1. Hoffmann M, Kleine‐Weber H, Schroeder S, et al. SARS‐CoV‐2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271‐280.e8. - PMC - PubMed

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

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

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