Elimination or Prolongation of ACE Inhibitors and ARB in Coronavirus Disease 2019 (REPLACECOVID)

The Randomized Elimination or Prolongation of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Coronavirus Disease 2019

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with a high incidence of acute respiratory distress syndrome (ARDS) and death. Hypertension and cardiovascular disease are risk factors for death in COVID-19. Angiotensin converting enzyme 2 (ACE2), an important component of the renin-angiotensin system, serves as the binding site of SARS-CoV-2 and facilitates host cell entry in the lungs. In experimental models, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to increase ACE2 expression in several organs, potentially promoting viral cell invasion, although these findings are not consistent across studies. Alternatively, ACEIs and ARBs may actually improve mechanisms of host defense or hyperinflammation, ultimately reducing organ injury. Finally, ACEIs and ARBs may have direct renal, pulmonary and cardiac protective benefits in the setting of COVID-19. Therefore, it is unclear if ACEIs and ARBs may be beneficial or harmful in patients with COVID-19. Given the high prevalence of hypertension, cardiovascular and renal disease in the world, the high prevalence of ACEIs or ARBs in these conditions, and the clinical equipoise regarding the continuation vs. discontinuation of ACEIs/ARBs in the setting of COVID, a randomized trial is urgently needed. The aim of this trial is to assess the clinical impact of continuation vs. discontinuation of ACE inhibitors and angiotensin receptor blockers on outcomes in patients hospitalized with COVID-19.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Other: Discontinuation of ARB/ACEI; Other: Continuation of ARB/ACEI

• Study Type: Interventional
• Enrollment (Actual): 152
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 years or older
2. Hospitalization with a suspected diagnosis of COVID-19, based on: (a) A compatible clinical presentation with a positive laboratory test for SARS-CoV-2, or (b) Considered by the primary team to be a Person Under Investigation due to undergo testing for COVID-19 in addition to compatible pulmonary infiltrates on chest x-ray (mutilobar, intersticial or ground glass opacities).
3. Use of ACEI or ARB as an outpatient prior to hospital admission.

Exclusion Criteria:

1. Systolic blood pressure <100 mmHg.
2. Systolic blood pressure > 180 mmHg or >160 if unable to substitute ACEIs/ARBs for another antihypertensive class, per the investigator's discretion.
3. Diastolic blood pressure > 110 mmHg
4. Known history of heart failure with reduced ejection fraction (EF <40%) on their most recent echo and/or clinical heart failure with unknown EF (i.e. no echo in approximately the past year).
5. Serum K>5.0 mEq/L on admission.
6. Known pregnancy or breastfeeding.
7. eGFR <30 mL/min/1.73m2
8. >50% increase in creatinine (to a creatinine >1.5 mg/dl) compared to most recent creatinine in the past six months, if available
9. Urine protein-to-creatitine ratio > 3 g/g or proteinuria > 3 g/24-hours within the past year
10. Ongoing treatment with aliskiren or sacubitril-valsartan.
11. Inability to obtain informed consent from patient.
12. Inability to read and write or lack of access to a smart phone, computer or tablet device at the time of evaluation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Discontinuation arm; The randomized intervention will be the discontinuation of ACEI/ARBs	Other: Discontinuation of ARB/ACEI; The randomized intervention will be the discontinuation of ACEI/ARBs. In all participants randomized to discontinuation, treating clinicians will be reminded about the medication discontinuation upon discharge and will be prompted to consider re-initiation of the medication at that time if appropriate, per the clinician's discretion.
Experimental: Continuation arm; The randomized intervention will be the continuation of ACEI/ARBs	Other: Continuation of ARB/ACEI; The randomized intervention will be the continuation of ACEI/ARBs at the doses previously prescribed for patients during their routine care. Clinicians will be encouraged to continue the randomized treatment but will be allowed to change the dose of ACEI/ARB or discontinue these medications if any compelling clinical reasons are identified (such as hypotension, hyperkalemia, acute kidney injury).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hierarchical Composite Endpoint	The primary endpoint of the trial will be a global rank based on patient outcomes according to four factors: (1) time to death, (2) the number of days supported by invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), (3) the number of days supported by renal replacement therapy or pressor/inotropic therapy, and (4) a modified sequential Organ Failure Assessment (SOFA) score. The modified SOFA score will include the cardiac, respiratory, renal and coagulation domains of the SOFA score. How to interpret the rank?: patients are ranked from worst to best outcomes, such that patients with bad outcomes are ranked at the top and patients who have the best outcomes are ranked at the bottom.	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-Cause Death		Up to 28 days
Length of Hospital Stay	This outcome measurement looked at the median length of hospitalization.	Up to 28 days
Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation		Up to 28 days
AUC SOFA	The Area Under the Curve of the modified SOFA (AUC SOFA) from daily measurements, weighted to account for the shorter observation period among patients who die in-hospital. How to interpret the AUC SOFA?: a higher area indicates more severe disease and/or longer hospitalization.The range is 0.1 to 377.3.	Up to 28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation.	Need to be transferred to an intensive care unit or to supported by a breathing machine	Up to 28 days
Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support	Hypotension Requiring Vasopressors, inotropes or mechanical hemodynamic support (ventricular assist device or intra-aortic balloon pump).	Up to 28 days

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: University of Arizona; Jordana B. Cohen, MD, MSCE; Thomas C. Hanff, MD, MPH; Department of Medicine, Hospital Nacional Carlos Alberto Seguín Escobedo, Arequipa, Peru; Department of Nephrology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru; Hypertension Unit, Department of Pathology, Hospital Español de Mendoza, National University of Cuyo, IMBECU-CONICET, Mendoza, Argentina; Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA; Division of Infectious Diseases, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada; Unidad de VIH, Hospital Civil de Guadalajara and Universidad de Guadalajara, Guadalajara, Mexico; Universidad Católica de Buenos Aires, Buenos Aires, Argentina; Departamento de Medicina Interna, Hospital Obrero number 3 Caja Nacional de Salud, Santa Cruz de la Sierra, Bolivia; Departamento de Medicina, Hospital Alberto Barton Thompson, Callao, Peru; Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden; Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA; Departamento de Emergencia, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru; Division of Cardiology, Department of Medicine, Hospital Español, Buenos Aires, Argentina; Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Jesse Chittams, MS; Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Charles R Vasquez, MD

Publications and helpful links

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Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2020
• Primary Completion (Actual): August 20, 2020
• Study Completion (Actual): August 20, 2020

Study Registration Dates

• First Submitted: April 1, 2020
• First Submitted That Met QC Criteria: April 7, 2020
• First Posted (Actual): April 8, 2020

Study Record Updates

• Last Update Posted (Actual): April 9, 2021
• Last Update Submitted That Met QC Criteria: April 7, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors
• Other Study ID Numbers: 842810

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Not making it available

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No