Effects of Discontinuing Renin-angiotensin System Inhibitors in Patients With and Without COVID-19 (RASCOVID-19)

Recent data from some of the earliest and worst affected countries of COVID-19 suggest a major overrepresentation of hypertension and diabetes among COVID-19-related deaths and among patients experiencing severe courses of the disease. The vast majority of patients with hypertension and/or diabetes are taking drugs targeting the renin-angiotensin system (RAS) because of their blood pressure-lowering and/or kidney-protective effects. Importantly, the virus causing COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the transmembrane protein angiotensin converting enzyme 2 (ACE2) - an important component of RAS - for host cell entry and subsequent viral replication. ACE2 is normally considered to be an enzyme that limits airway inflammation via effects in RAS and increased ACE2 activity seems to alleviate acute respiratory distress syndrome (ARDS). Importantly, evidence from human studies as well as rodent studies suggests that the inhibition of RAS by angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) leads to upregulation of ACE2, and treatment with ARB leads to attenuation of SARS-CoV-induced ARDS. This is of interest, as the vast majority of deaths from COVID-19 are due to ARDS and expression of ACE2 has previously been shown to be reduced by the binding of SARS-CoV to ACE2. Thus, ACE inhibitors and ARBs have been suggested to alleviate the COVID-19 pulmonary manifestations. In contrast to these notions, concern has been raised that ACE2 upregulation (by RAS-inhibiting drugs) will multiply the cellular access points for viral entry and might increase the risk of severe progression of COVID-19. The multiplied viral entry points could perhaps explain the alarmingly high morbidity and mortality among COVID-19 patients with diabetes and/or hypertension. Thus, a delineation of the role of RAS for the course of COVID-19 is of crucial importance for the management of COVID-19 patients.

Aim:

This randomised clinical trial will investigate whether to continue or discontinue treatment with ACE inhibitors or ARBs in hospitalised patients with COVID-19.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Capital Region Of Denmark
    • Hellerup, Capital Region Of Denmark, Denmark, 2900
      • Department of Medicine, Gentofte Hospital, University of Copenhagen
    • Herlev, Capital Region Of Denmark, Denmark, 2730
      • Department of Medicine, Herlev Hospital, University of Copenhagen

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

Group A and B

Inclusion Criteria:

1. Verified COVID-19
2. Hospital admitted
3. Daily administration of RAS-inhibiting therapy
4. Age 18 years and above
5. Informed consent

Exclusion Criteria:

1. Diagnosed with systolic heart failure (heart failure with reduced ejection fraction)
2. Severe kidney disease; defined by estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2
3. Severe hypertension; defined by systolic pressure >175 mm Hg and/or diastolic pressure >105 mm Hg
4. Hypotension; defined by systolic pressure <100 mm Hg and/or diastolic pressure <60 mm Hg
5. Non-compliance of RAS-inhibiting therapy; defined as an estimated adherence <80% assessed by a questionnaire in combination with checking the Danish electronic medication system "FMK" (obligatory for clinicians in Denmark to ensure the Danish electronic medication system "FMK" is correct and up-to-date) for redeemed prescriptions in the last six months; in borderline cases, the participant is assumed compatible
6. Pregnancy or breastfeeding

7. Contra indications for receiving ACE inhibitors or ARBs:

   1. Severe liver disease
   2. Hypersensitivity or allergic reactions to the therapy
   3. Angioneurotic edema during previous treatments
   4. Family history of or previous idiopathic angioneurotic edema
   5. Treatment with sacubitril/valsartan or aliskiren

Group C and D:

Inclusion Criteria:

1. Daily administration of RAS-inhibiting therapy
2. Age 18 years and above
3. Informed consent

Exclusion Criteria:

1. Diagnosed with systolic heart failure (heart failure with reduced ejection fraction)
2. Severe kidney disease; defined by estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2
3. Severe hypertension; defined by systolic pressure >175 mm Hg and/or diastolic pressure >105 mm Hg
4. Hypotension; defined by systolic pressure <100 mm Hg and/or diastolic pressure <60 mm Hg
5. Non-compliance of RAS-inhibiting therapy; defined as an estimated adherence <80% assessed by a questionnaire in combination with checking the Danish electronic medication system "FMK" (obligatory for clinicians in Denmark to ensure the Danish electronic medication system "FMK" is correct and up-to-date) for redeemed prescriptions in the last six months; in borderline cases, the participant is assumed compatible
6. Pregnancy or breastfeeding

7. Contra indications for receiving ACE inhibitors or ARBs:

   1. Severe liver disease
   2. Hypersensitivity or allergic reactions to the therapy
   3. Angioneurotic edema during previous treatments
   4. Family history of or previous idiopathic angioneurotic edema
   5. Treatment with sacubitril/valsartan or aliskiren

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A: COVID+ Continuation; The enrolled patients will continue their prescribed ACEi/ARB in the same dose. The clinicians will be encouraged to continue the medication throughout the hospital admission but it will be permissable for the clinician to stop treatment if necessary e.g. due to hypotension.	Other: Continuation of ACEi/ARB; Continuation of ACEi/ARB
Experimental: B: Covid+ Discontinuation; The enrolled patients will discontinue their prescribed ACEi/ARB. If hypertensive treatment is necessary during hospital admission the clinicians will first be encouraged to start non-ACEi/non-ARB treatment; however, if needed it will be possible to start ACEi/ARB again during hospital admission. After study completion (30 days from randomization) the patients will be reminded to seek their generel practitioner to reinitiate ACEi/ARB treatment.	Other: Discontinuation of ACEi/ARB; Discontinuation of ACEi/ARB
Experimental: C: COVID% Continuation; The enrolled patients will continue their prescribed ACEi/ARB in the same dose.	Other: Continuation of ACEi/ARB; Continuation of ACEi/ARB
Experimental: D: COVID% DIscontinuation; The enrolled patients will discontinue their prescribed ACEi/ARB. If hypertensive treatment is necessary during the study period clinicians will first be encouraged to start non-ACEi/non-ARB treatment; however, if needed it will be possible to start ACEi/ARB again during the study period. After study completion (30 days from randomization) the patients will be reminded to seek their generel practitioner to reinitiate ACEi/ARB treatment.	Other: Discontinuation of ACEi/ARB; Discontinuation of ACEi/ARB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive and out of hospital within 14 days after recruitment (group A vs. group B).	The primary endpoint is days alive and out of hospital within 14 days after recruitment on which a patient satisfies categories 0, 1 or 2 on the eight-category ordinal scale. WHO defined Ordinal Scale for Clinical Improvement: 0. Not hospitalized, no clinical or virological evidence of infection; Not hospitalized, no limitations of activities; Not hospitalized, limitation of activities; Hospitalized, no oxygen therapy; Hospitalized, oxygen by mask or nasal prongs; Hospitalized, non-invasive ventilation or high-flow oxygen; Hospitalized, intubation and mechanical ventilation; Hospitalized, ventilation and additional organ support - pressors, rapid response team (RRT), extracorporeal membrane oxygenation (ECMO); Death	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Key-secondary composite endpoint: Occurrence of worsening of COVID-19 (group A vs. group B)	The key-secondary composite endpoint is the occurrence of worsening of COVID-19 (group A vs. group B) as assessed by when a patient satisfies category 6, 7 or 8 on the ordinal scale within the trial period.	30 days
Occurrence and time to occurrence of each of the components of the key-secondary composite endpoint (group A vs. group B)	Occurrence and time to occurrence of each of the components of the key-secondary composite endpoint	30 days
Kidney function assessed by plasma creatinine (group A vs. group B)	Kidney function assessed by plasma creatinine	30 days
Duration of index hospitalisation (group A vs. group B)	Duration of index hospitalisation	30 days
30-day mortality (group A vs. group B)	30-day mortality	30 days
Number of days alive during the intervention period (group A vs. group B)	Number of days alive during the intervention period	30 days
Number of participants not yet discharged at day 30 (group A vs. group B)	Number of participants not yet discharged at day 30	30 days
Number of readmissions after 30 days. (group A vs. group B)	Number of readmissions after 30 days.	30 days
Kidney function as assessed by eGFR (group A vs. group B)	Kidney function as assessed by eGFR	30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Support for clinical findings via relevant blood markers	To support the clinical findings, blood samples will be analysed for ACE, ACE2, aldosterone, angiotensin II and renin, and expression of ACE, interferon signatures and T cell exhaustion markers.	30 days

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen
• Investigators: Principal Investigator: Filip K Knop, MD, PhD, Center for Clinical Metabolic Research, Gentofte Hospital

Publications and helpful links

General Publications

• Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020 Apr;46(4):586-590. doi: 10.1007/s00134-020-05985-9. Epub 2020 Mar 3. No abstract available.
• Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005 Jul 7;436(7047):112-6. doi: 10.1038/nature03712.
• Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, Shibata S, Tanaka M, Watanabe Y, Akasaka H, Ohnishi H, Yoshida H, Takizawa H, Saitoh S, Ura N, Shimamoto K, Miura T. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens. 2015 Jan;28(1):15-21. doi: 10.1093/ajh/hpu086. Epub 2014 May 18.
• Vuille-dit-Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, Hamie QM, Meier CF, Hunziker S, Forras-Kaufmann Z, Kuyumcu S, Fox M, Schwizer W, Fried M, Lindenmeyer M, Gotze O, Verrey F. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids. 2015 Apr;47(4):693-705. doi: 10.1007/s00726-014-1889-6. Epub 2014 Dec 23.

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2020
• Primary Completion (Actual): December 22, 2022
• Study Completion (Actual): December 22, 2022

Study Registration Dates

• First Submitted: April 14, 2020
• First Submitted That Met QC Criteria: April 14, 2020
• First Posted (Actual): April 17, 2020

Study Record Updates

• Last Update Posted (Actual): January 18, 2023
• Last Update Submitted That Met QC Criteria: January 17, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: COVID-19; Angiotensin converting enzyme inhibitor; ARB; RAS; ACEi; Renin-angiotensin system; Angiotensin II receptor blocker
• 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: H-20026484; 2020-001544-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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