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

Study Overview
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Brief Summary
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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.

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

Conditions
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Covid-19

Intervention / Treatment
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* Other: Discontinuation of ACEi/ARB
* Other: Continuation of ACEi/ARB


Participation Criteria
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Eligibility Criteria
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Group A and B Inclusion Criteria: Verified COVID-19 Hospital admitted Daily administration of RAS-inhibiting therapy Age 18 years and above Informed consent Exclusion Criteria: 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: Inclusion Criteria: Daily administration of RAS-inhibiting therapy Age 18 years and above Informed consent Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: COVID+ Continuation<br>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<br>* Continuation of ACEi/ARB<br>|
| Experimental: B: Covid+ Discontinuation<br>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<br>* Discontinuation of ACEi/ARB<br>|
| Experimental: C: COVID% Continuation<br>The enrolled patients will continue their prescribed ACEi/ARB in the same dose. | Other: Continuation of ACEi/ARB<br>* Continuation of ACEi/ARB<br>|
| Experimental: D: COVID% DIscontinuation<br>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<br>* Discontinuation of ACEi/ARB<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angiotensin converting enzyme inhibitor, ARB, ACEi, COVID-19, RAS, Renin-angiotensin system, Angiotensin II receptor blocker