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

NCT04351581 | Completed DMC

• 2 other identifiers: H-200264842020-001544-26
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Covid-19

Keywords

COVID-19; RAS; Renin-angiotensin system; Angiotensin II receptor blocker; Angiotensin converting enzyme inhibitor; ARB; ACEi

Outcome Measures

Primary Outcomes (1)

• 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 1. Not hospitalized, no limitations of activities 2. Not hospitalized, limitation of activities 3. Hospitalized, no oxygen therapy 4. Hospitalized, oxygen by mask or nasal prongs 5. Hospitalized, non-invasive ventilation or high-flow oxygen 6. Hospitalized, intubation and mechanical ventilation 7. Hospitalized, ventilation and additional organ support - pressors, rapid response team (RRT), extracorporeal membrane oxygenation (ECMO) 8. Death

  14 days

Secondary Outcomes (9)

• Key-secondary composite endpoint: Occurrence of worsening of COVID-19 (group A vs. group B)

  30 days

• Occurrence and time to occurrence of each of the components of the key-secondary composite endpoint (group A vs. group B)

  30 days

• Kidney function assessed by plasma creatinine (group A vs. group B)

  30 days

• Duration of index hospitalisation (group A vs. group B)

  30 days

• 30-day mortality (group A vs. group B)

  30 days

Other Outcomes (1)

• Support for clinical findings via relevant blood markers

  30 days

Study Arms (4)

A: COVID+ Continuation

EXPERIMENTAL

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

B: Covid+ Discontinuation

EXPERIMENTAL

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

C: COVID% Continuation

EXPERIMENTAL

The enrolled patients will continue their prescribed ACEi/ARB in the same dose.

Other: Continuation of ACEi/ARB

D: COVID% DIscontinuation

EXPERIMENTAL

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

Interventions

Discontinuation of ACEi/ARB OTHER

Discontinuation of ACEi/ARB

B: Covid+ Discontinuation; D: COVID% DIscontinuation

Continuation of ACEi/ARB OTHER

Continuation of ACEi/ARB

A: COVID+ Continuation; C: COVID% Continuation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Verified COVID-19
• Hospital admitted
• Daily administration of RAS-inhibiting therapy
• Age 18 years and above
• Informed consent

You may not qualify if:

• Diagnosed with systolic heart failure (heart failure with reduced ejection fraction)
• Severe kidney disease; defined by estimated glomerular filtration rate (eGFR) \<30 ml/min/1.73 m2
• Severe hypertension; defined by systolic pressure \>175 mm Hg and/or diastolic pressure \>105 mm Hg
• Hypotension; defined by systolic pressure \<100 mm Hg and/or diastolic pressure \<60 mm Hg
• 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
• Pregnancy or breastfeeding
• Contra indications for receiving ACE inhibitors or ARBs:
• Severe liver disease
• Hypersensitivity or allergic reactions to the therapy
• Angioneurotic edema during previous treatments
• Family history of or previous idiopathic angioneurotic edema
• Treatment with sacubitril/valsartan or aliskiren
• Group C and D:
• Daily administration of RAS-inhibiting therapy
• Age 18 years and above

Sponsors & Collaborators

• University Hospital, Gentofte, Copenhagen: lead

Study Sites (2)

Department of Medicine, Gentofte Hospital, University of Copenhagen

Hellerup, Capital Region of Denmark, 2900, Denmark

Location

Department of Medicine, Herlev Hospital, University of Copenhagen

Herlev, Capital Region of Denmark, 2730, Denmark

Location

Related Publications (5)

• 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.

  PMID: 32125455 BACKGROUND

• 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.

  PMID: 16001071 BACKGROUND

• 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.

  PMID: 24842388 BACKGROUND

• 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.

  PMID: 25534429 BACKGROUND

• Kliim-Hansen V, Gasbjerg LS, Ellegaard AM, Lorentsson HJN, Lynggaard MB, Hagemann CA, Legart C, Mathiesen DS, Sivapalan P, Jensen JS, Vilsboll T, Christensen MB, Knop FK. Protocol for a 30-day randomised, parallel-group, non-inferiority, controlled trial investigating the effects of discontinuing renin-angiotensin system inhibitors in patients with and without COVID-19: the RASCOVID-19 trial. BMJ Open. 2022 Nov 30;12(11):e062895. doi: 10.1136/bmjopen-2022-062895.

  PMID: 36450422 DERIVED

MeSH Terms

Conditions

COVID-19

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Filip K Knop, MD, PhD

  Center for Clinical Metabolic Research, Gentofte Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, MD, PhD

Study Record Dates

• First Submitted: April 14, 2020
• First Posted: April 17, 2020
• Study Start: May 18, 2020
• Primary Completion: December 22, 2022
• Study Completion: December 22, 2022
• Last Updated: January 18, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

DK (2)