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

COVID-19 Clinical Trial

— REPLACECOVID  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04338009
• Other study ID #: 842810
• Status: Completed
• Phase: N/A
• Start date: March 31, 2020
• Est. completion date: August 20, 2020

Study information

• Verified date: April 2021
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 152
• Est. completion date: August 20, 2020
• Est. primary completion date: August 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Coronavirus Infections
• COVID-19

Intervention

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.
• 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).

Locations

Country	Name	City	State
United States	University of Pennsylvania Health System	Philadelphia	Pennsylvania

Sponsors (21)

Lead Sponsor

Collaborator

University of Pennsylvania

Charles R Vasquez, MD, Departamento de Emergencia, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru, 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, Department of Medicine, Hospital Nacional Carlos Alberto Seguín Escobedo, Arequipa, Peru, Department of Nephrology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru, Division of Cardiology, Department of Medicine, Hospital Español, Buenos Aires, Argentina, Division of Cardiology, University of Arizona, Tucson, AZ, USA, Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA, Division of Infectious Diseases, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA, Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA, Hypertension Unit, Department of Pathology, Hospital Español de Mendoza, National University of Cuyo, IMBECU-CONICET, Mendoza, Argentina, Jesse Chittams, MS, Jordana B. Cohen, MD, MSCE, Thomas C. Hanff, MD, MPH, Unidad de VIH, Hospital Civil de Guadalajara and Universidad de Guadalajara, Guadalajara, Mexico, Universidad Católica de Buenos Aires, Buenos Aires, Argentina

Country where clinical trial is conducted

United States, 

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* Note: There are 39 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Primary	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	All-Cause Death		Up to 28 days
Secondary	Length of Hospital Stay	This outcome measurement looked at the median length of hospitalization.	Up to 28 days
Secondary	Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation		Up to 28 days
Secondary	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