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


Eligibility Criteria:
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