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

Study Overview
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Brief Summary
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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.

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

Conditions
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COVID-19

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older 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). Use of ACEI or ARB as an outpatient prior to hospital admission. Exclusion Criteria: Systolic blood pressure <100 mmHg. Systolic blood pressure > 180 mmHg or >160 if unable to substitute ACEIs/ARBs for another antihypertensive class, per the investigator's discretion. Diastolic blood pressure > 110 mmHg 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). Serum K>5.0 mEq/L on admission. Known pregnancy or breastfeeding. eGFR <30 mL/min/1.73m2 >50% increase in creatinine (to a creatinine >1.5 mg/dl) compared to most recent creatinine in the past six months, if available Urine protein-to-creatitine ratio > 3 g/g or proteinuria > 3 g/24-hours within the past year Ongoing treatment with aliskiren or sacubitril-valsartan. Inability to obtain informed consent from patient. Inability to read and write or lack of access to a smart phone, computer or tablet device at the time of evaluation.

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: Discontinuation arm<br>The randomized intervention will be the discontinuation of ACEI/ARBs | Other: Discontinuation of ARB/ACEI<br>* 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.<br>|
| Experimental: Continuation arm<br>The randomized intervention will be the continuation of ACEI/ARBs | Other: Continuation of ARB/ACEI<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-Cause Death |  | Up to 28 days | 
| Length of Hospital Stay | This outcome measurement looked at the median length of hospitalization. | Up to 28 days | 
| Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation |  | Up to 28 days | 
| 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 |