COVID-19, SARS-CoV-2
Conditions
Keywords
ACE-inhibitors, RAS system, angiotensin receptor blockers, SARS-CoV-2, COVID-19
Brief summary
ACEI-COVID-19 is a multicenter, randomized trial testing the hypothesis that stopping/replacing chronic treatment with ACE-inhibitors (ACEI) or angiotensin receptor blockers (ARB) improves outcomes in symptomatic SARS-CoV2-infected patients
Detailed description
The COVID-19 pandemic currently poses unprecedented challenges to the health systems of all countries. Experimental studies show that the SARS-CoV2 virus enters human cells via the angiotensin converting enzyme II receptor 2 (ACE2). ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) can lead to an increase in the expression of ACE2. Therefore, there is concern that in patients treated with ACEI or ARB, the absorption of the virus is facilitated, thereby accelerating its spread in the body. ACEI-COVID tests the hypothesis that stopping chronic ACEI / ARB therapy in SARS-CoV2-infected patients improves outcomes.
Interventions
DRUGACE inhibitor, angiotensin receptor blocker
In patients randomized to stopping / replacing ACEI or ARB, it may be necessary to switch to another drug without direct effect on the RAS system. In patients, randomized to continuation, it may be needed to stop ACEI or ARB (e.g. hypotension with beginning sepsis) irrespective of the study.
Sponsors
Ludwig-Maximilians - University of Munich
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Medical University Innsbruck
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
unmasked
Intervention model description
open-label, randomized design
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female and male patients competent to make a decision * Proven and symptomatic SARS-CoV2 infection ≤ 5 days * Patient age ≥ 18 years * Provided written informed consent * Chronic (≥ 1 month) ACEI/ARB therapy for treatment of arterial hypertension, diabetes mellitus, heart failure or coronary artery disease * Stable hemodynamic conditions allowing to stop or continue treatment with ACEI/ARB (systolic blood pressure ≤180mmHg)
Exclusion criteria
* Women capable of bearing children as well as pregnant and breastfeeding women * Participant in another interventional trail * At screening visit, no oral medication intake possible * Advanced heart failure NYHA Stage III-IV * Left ventricular ejection fraction \<30% or NTproBNP ≥600pg/mL in case of clinical signs of heart failure * Acute coronary syndrome ≤ 3 months * Severe arterial hypertension (concomitant use of more than 4 different antihypertensive drug classes) * Acute respiratory distress syndrome with need for mechanical ventilation * Patients who at not capable of home blood pressure monitoring * Patients who cannot be switched to an alternative medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of the Maximum Sequential Organ Failure Assessment (SOFA) Score and Death Within 30 Days | 30 days | The score is calculated from six different components, each of which reflects the status of an organ system, including respiratory function, cardiovascular integrity, liver function, coagulation, renal function and neurological status. The score can range from 0 (best) to 24 (worst). In case of death, the patient was by definition assigned the maximum value of 24. Outpatients were assigned a value of 0 or 24 (in the case of death). |
| Composite of Admission to an Intensive Care Unit (ICU), the Use of Mechanical Ventilation, or All-cause Death | 30 days | Composite of admission to ICU, mechanical ventilation, and death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rates of Renal Replacement Therapies | 30 days | — |
| Number of Patients With Systolic/Diastolic Blood Pressure > 180/120 mmHg | 30 days | — |
| Mean of Sequential Organ Failure Assessment (SOFA) Score | 30 days | minimum score is 0, maximum score is 24; higher score indicates poor outcome (death-adjusted) |
| Rates of Mechanical Ventilation | 30 days | — |
| Hospitalisation Due to Cardiac Decompensation | 30 days | with causal relationship to stopping of ACEI/ARB therapy |
| Rates of Non-invasive Ventilation | 30 days | Number of Participants with Non-invasive Ventilation |
Countries
Austria, Germany
Participant flow
Recruitment details
Between April 20, 2020, and Jan 20, 2021, 204 participants were randomly assigned to discontinuation (n=109) or continuation (n=107) of RAS inhibition, at 35 centres, including 19 university clinics and 16 large referral hospitals, in Austria and Germany.
Pre-assignment details
Of 2301 patients, who were assessed for eligibility, 216 underwent randomization. 1921 were excluded due violation of inclusion or exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Discontinuation Group Chronic pretreatment with ACEI or ARB will be stopped or replaced.
Substitution with an alternative substance class was at the discretion of the treating physician | 104 |
| Continuation Group No intervention, which means further treatment with ACEI or ARB. In patients, randomized to continuation, it may be needed to stop ACEI or ARB (e.g. hypotension with beginning sepsis) irrespective of the study. | 100 |
| Total | 204 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | no evidence of recent SARS-CoV-2 | 1 | 3 |
| Overall Study | Protocol Violation | 4 | 4 |
Baseline characteristics
| Characteristic | Discontinuation Group | Continuation Group | Total |
|---|---|---|---|
| Age, Continuous | 74 years | 75 years | 75 years |
| Angiotensin-converting enzyme inhibitor | 57 Participants | 58 Participants | 115 Participants |
| Angiotensin II receptor blocker | 47 Participants | 42 Participants | 89 Participants |
| Atrial fibrillation | 18 Participants | 17 Participants | 35 Participants |
| BMI | 28 kg per m^2 | 27.4 kg per m^2 | 27.6 kg per m^2 |
| Chronic obstructive pulmonary disease | 10 Participants | 22 Participants | 32 Participants |
| Coronary artery disease | 22 Participants | 23 Participants | 45 Participants |
| Current Smoker | 6 Participants | 99 Participants | 105 Participants |
| Diabetes | 30 Participants | 37 Participants | 67 Participants |
| Dyslipidaemia | 38 Participants | 48 Participants | 86 Participants |
| Heart failure | 12 Participants | 6 Participants | 18 Participants |
| History of stroke | 8 Participants | 5 Participants | 13 Participants |
| Hypertension | 100 Participants | 99 Participants | 199 Participants |
| Kidney disease | 16 Participants | 21 Participants | 37 Participants |
| Malignant disease | 7 Participants | 13 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 104 Participants | 100 Participants | 204 Participants |
| Region of Enrollment Austria | 59 participants | 57 participants | 116 participants |
| Region of Enrollment Germany | 45 participants | 43 participants | 88 participants |
| Sex: Female, Male Female | 39 Participants | 36 Participants | 75 Participants |
| Sex: Female, Male Male | 65 Participants | 64 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 104 | 12 / 100 |
| other Total, other adverse events | 13 / 104 | 7 / 100 |
| serious Total, serious adverse events | 25 / 104 | 28 / 100 |
Outcome results
Primary
Composite of Admission to an Intensive Care Unit (ICU), the Use of Mechanical Ventilation, or All-cause Death
Composite of admission to ICU, mechanical ventilation, and death
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Discontinuation Group | Composite of Admission to an Intensive Care Unit (ICU), the Use of Mechanical Ventilation, or All-cause Death | 21 Participants |
| Continuation Group | Composite of Admission to an Intensive Care Unit (ICU), the Use of Mechanical Ventilation, or All-cause Death | 26 Participants |
Primary
Composite of the Maximum Sequential Organ Failure Assessment (SOFA) Score and Death Within 30 Days
The score is calculated from six different components, each of which reflects the status of an organ system, including respiratory function, cardiovascular integrity, liver function, coagulation, renal function and neurological status. The score can range from 0 (best) to 24 (worst). In case of death, the patient was by definition assigned the maximum value of 24. Outpatients were assigned a value of 0 or 24 (in the case of death).
Time frame: 30 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Discontinuation Group | Composite of the Maximum Sequential Organ Failure Assessment (SOFA) Score and Death Within 30 Days | 0 score on a scale |
| Continuation Group | Composite of the Maximum Sequential Organ Failure Assessment (SOFA) Score and Death Within 30 Days | 1 score on a scale |
Secondary
Hospitalisation Due to Cardiac Decompensation
with causal relationship to stopping of ACEI/ARB therapy
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Discontinuation Group | Hospitalisation Due to Cardiac Decompensation | 0 Participants |
| Continuation Group | Hospitalisation Due to Cardiac Decompensation | 0 Participants |
Secondary
Mean of Sequential Organ Failure Assessment (SOFA) Score
minimum score is 0, maximum score is 24; higher score indicates poor outcome (death-adjusted)
Time frame: 30 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Discontinuation Group | Mean of Sequential Organ Failure Assessment (SOFA) Score | 0 score on a scale |
| Continuation Group | Mean of Sequential Organ Failure Assessment (SOFA) Score | 0.12 score on a scale |
Secondary
Number of Patients With Systolic/Diastolic Blood Pressure > 180/120 mmHg
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Discontinuation Group | Number of Patients With Systolic/Diastolic Blood Pressure > 180/120 mmHg | 7 Participants |
| Continuation Group | Number of Patients With Systolic/Diastolic Blood Pressure > 180/120 mmHg | 7 Participants |
Secondary
Rates of Mechanical Ventilation
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Discontinuation Group | Rates of Mechanical Ventilation | 10 Participants |
| Continuation Group | Rates of Mechanical Ventilation | 8 Participants |
Secondary
Rates of Non-invasive Ventilation
Number of Participants with Non-invasive Ventilation
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Discontinuation Group | Rates of Non-invasive Ventilation | 19 Participants |
| Continuation Group | Rates of Non-invasive Ventilation | 14 Participants |
Secondary
Rates of Renal Replacement Therapies
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Discontinuation Group | Rates of Renal Replacement Therapies | 0 Participants |
| Continuation Group | Rates of Renal Replacement Therapies | 1 Participants |