COVID-19
Conditions
Brief summary
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.
Interventions
OTHERDiscontinuation of ARB/ACEI
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.
OTHERContinuation of ARB/ACEI
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).
Sponsors
Jordana B. Cohen, MD, MSCE
Hanff, Thomas C., M.D., MPH
University of Arizona
Hospital Nacional Carlos Alberto Seguin Escobedo - EsSalud
Hospital Nacional Edgardo Rebagliati Martins
Hospital Español de Mendoza
Stanford University
Ottawa Hospital Research Institute
Hospital Civil de Guadalajara
Universidad Catolica Argentina
Caja Nacional de Salud
Departamento de Medicina, Hospital Alberto Barton Thompson, Callao, Peru
Karolinska Institutet
University of Miami
Division of Cardiology, Department of Medicine, Hospital Español, Buenos Aires, Argentina
University of Michigan
Jesse Chittams, MS
Duke University
Vasquez, Charles R., M.D.
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 years or older 2. 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). 3. Use of ACEI or ARB as an outpatient prior to hospital admission.
Exclusion criteria
1. Systolic blood pressure \<100 mmHg. 2. Systolic blood pressure \> 180 mmHg or \>160 if unable to substitute ACEIs/ARBs for another antihypertensive class, per the investigator's discretion. 3. Diastolic blood pressure \> 110 mmHg 4. 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). 5. Serum K\>5.0 mEq/L on admission. 6. Known pregnancy or breastfeeding. 7. eGFR \<30 mL/min/1.73m2 8. \>50% increase in creatinine (to a creatinine \>1.5 mg/dl) compared to most recent creatinine in the past six months, if available 9. Urine protein-to-creatitine ratio \> 3 g/g or proteinuria \> 3 g/24-hours within the past year 10. Ongoing treatment with aliskiren or sacubitril-valsartan. 11. Inability to obtain informed consent from patient. 12. Inability to read and write or lack of access to a smart phone, computer or tablet device at the time of evaluation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hierarchical Composite Endpoint | Up to 28 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-Cause Death | Up to 28 days | — |
| Length of Hospital Stay | Up to 28 days | This outcome measurement looked at the median length of hospitalization. |
| Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation | Up to 28 days | — |
| AUC SOFA | Up to 28 days | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation. | Up to 28 days | Need to be transferred to an intensive care unit or to supported by a breathing machine |
| Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support | Up to 28 days | Hypotension Requiring Vasopressors, inotropes or mechanical hemodynamic support (ventricular assist device or intra-aortic balloon pump). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Discontinuation Arm The randomized intervention will be the discontinuation of ACEI/ARBs
Discontinuation of ARB/ACEI: 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. | 77 |
| Continuation Arm The randomized intervention will be the continuation of ACEI/ARBs
Continuation of ARB/ACEI: 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). | 75 |
| Total | 152 |
Baseline characteristics
| Characteristic | Continuation Arm | Discontinuation Arm | Total |
|---|---|---|---|
| Age, Customized Age | 62 years STANDARD_DEVIATION 12 | 62 years STANDARD_DEVIATION 12 | 62 years STANDARD_DEVIATION 12 |
| Atrial fibrillation | 3 Participants | 0 Participants | 3 Participants |
| BMI | 33 kg/m^2 STANDARD_DEVIATION 7 | 33 kg/m^2 STANDARD_DEVIATION 9 | 33 kg/m^2 STANDARD_DEVIATION 8 |
| Chronic pulmonary disease | 9 Participants | 17 Participants | 26 Participants |
| Cough | 59 Participants | 58 Participants | 117 Participants |
| C reactive protein | 48 mg/dL STANDARD_DEVIATION 68 | 45 mg/dL STANDARD_DEVIATION 77 | 46 mg/dL STANDARD_DEVIATION 72 |
| Current Smoker | 5 Participants | 8 Participants | 13 Participants |
| Days from admission to randomization | 1.6 days STANDARD_DEVIATION 0.9 | 1.5 days STANDARD_DEVIATION 0.5 | 1.5 days STANDARD_DEVIATION 0.7 |
| Days from symptom onset to randomization | 6.5 days STANDARD_DEVIATION 2.3 | 6.8 days STANDARD_DEVIATION 2.5 | 6.65 days STANDARD_DEVIATION 2.4 |
| Diabetes Insulin Therapy | 20 Participants | 16 Participants | 36 Participants |
| Diabetes No insulin therapy | 22 Participants | 11 Participants | 33 Participants |
| Diastolic BP | 75 mmHg STANDARD_DEVIATION 13 | 77 mmHg STANDARD_DEVIATION 12 | 76 mmHg STANDARD_DEVIATION 12 |
| Dyslipidemia | 34 Participants | 32 Participants | 66 Participants |
| Dyspnoea | 66 Participants | 66 Participants | 132 Participants |
| eGFR | 83 mL/min/1.73m^2 STANDARD_DEVIATION 23 | 81 mL/min/1.73m^2 STANDARD_DEVIATION 25 | 82 mL/min/1.73m^2 STANDARD_DEVIATION 24 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants | 42 Participants | 82 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 35 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Heart Failure | 3 Participants | 3 Participants | 6 Participants |
| Heart rate | 91 bpm STANDARD_DEVIATION 16 | 92 bpm STANDARD_DEVIATION 17 | 91 bpm STANDARD_DEVIATION 16 |
| Hypertension ACEI therapy (as opposed to ARB)* | 25 Participants | 38 Participants | 63 Participants |
| Hypertension Calcium channel blocker therapy | 20 Participants | 26 Participants | 46 Participants |
| Hypertension Diuretic therapy | 25 Participants | 21 Participants | 46 Participants |
| Hypertension Lowest recommended ACEI or ARB dose | 14 Participants | 14 Participants | 28 Participants |
| Hypertension β blocker therapy | 11 Participants | 14 Participants | 25 Participants |
| Illicit drug use | 2 Participants | 3 Participants | 5 Participants |
| Ischemic heart disease | 6 Participants | 12 Participants | 18 Participants |
| K Serum | 4 mmol/L STANDARD_DEVIATION 0.5 | 4 mmol/L STANDARD_DEVIATION 0.5 | 4 mmol/L STANDARD_DEVIATION 0.5 |
| Leukocyte count | 9.3 10^9 cells/L STANDARD_DEVIATION 4.3 | 8.9 10^9 cells/L STANDARD_DEVIATION 4.5 | 9.1 10^9 cells/L STANDARD_DEVIATION 4.4 |
| Multifocal infiltrates on chest x-ray or CT | 48 Participants | 43 Participants | 91 Participants |
| Obstructive sleep apnea | 7 Participants | 10 Participants | 17 Participants |
| Oxygen saturation | 92 % of oxygen in blood STANDARD_DEVIATION 8 | 92 % of oxygen in blood STANDARD_DEVIATION 5 | 92 % of oxygen in blood STANDARD_DEVIATION 7 |
| Oxygen supplementation | 63 number of subjects requiring extra O2 | 60 number of subjects requiring extra O2 | 61 number of subjects requiring extra O2 |
| Platelets | 239 10^3 cells/microL STANDARD_DEVIATION 109 | 238 10^3 cells/microL STANDARD_DEVIATION 130 | 238 10^3 cells/microL STANDARD_DEVIATION 119 |
| Pre-existing cardiac disease | 10 Participants | 14 Participants | 24 Participants |
| Previous PE or DVT | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Female | 33 Participants | 35 Participants | 68 Participants |
| Sex: Female, Male Male | 42 Participants | 42 Participants | 84 Participants |
| Systolic BP | 129 mmHg STANDARD_DEVIATION 19 | 133 mmHg STANDARD_DEVIATION 22 | 131 mmHg STANDARD_DEVIATION 20 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 77 | 11 / 75 |
| other Total, other adverse events | 0 / 77 | 0 / 75 |
| serious Total, serious adverse events | 28 / 77 | 29 / 75 |
Outcome results
Primary
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.
Time frame: Up to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Discontinuation Arm | Hierarchical Composite Endpoint | 81 score on a scale (range 1 to 152) |
| Continuation Arm | Hierarchical Composite Endpoint | 73 score on a scale (range 1 to 152) |
Secondary
All-Cause Death
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Discontinuation Arm | All-Cause Death | 10 Participants |
| Continuation Arm | All-Cause Death | 11 Participants |
Secondary
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.
Time frame: Up to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Discontinuation Arm | AUC SOFA | 7 units on a scale (SOFA x days) |
| Continuation Arm | AUC SOFA | 12 units on a scale (SOFA x days) |
Secondary
Length of Hospital Stay
This outcome measurement looked at the median length of hospitalization.
Time frame: Up to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Discontinuation Arm | Length of Hospital Stay | 5 days |
| Continuation Arm | Length of Hospital Stay | 6 days |
Secondary
Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation
Time frame: Up to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Discontinuation Arm | Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation | 15 days |
| Continuation Arm | Length of ICU Stay, Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation | 13 days |
Other Pre-specified
Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support
Hypotension Requiring Vasopressors, inotropes or mechanical hemodynamic support (ventricular assist device or intra-aortic balloon pump).
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Discontinuation Arm | Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support | 8 Participants |
| Continuation Arm | Hypotension Requiring Vasopressors, Inotropes or Mechanical Hemodynamic Support | 9 Participants |
Other Pre-specified
Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation.
Need to be transferred to an intensive care unit or to supported by a breathing machine
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Discontinuation Arm | Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation. | 14 Participants |
| Continuation Arm | Intensive Care Unit Admission or Respiratory Failure Requiring Mechanical Ventilation. | 16 Participants |