Stopping ACE-inhibitors in COVID-19 (ACEI-COVID)

Stopping ACE-inhibitors in COVID-19: A Randomized Controlled Trial

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

Study Overview

• Status: Completed
• Conditions: COVID-19; SARS-CoV-2
• Intervention / Treatment: Drug: ACE inhibitor, angiotensin receptor blocker

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.

• Study Type: Interventional
• Enrollment (Actual): 216
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
    • Medical University of Graz
  • Hall In Tirol, Austria
    • Landeskrankenhaus Hall
  • Innsbruck, Austria
    • Medical University Innsbruck, Intensive Care and Emergency Medicine Department
  • Innsbruck, Austria
    • Medical University Innsbruck, University Hospital of Internal Medicine II
  • Innsbruck, Austria
    • Medical University Innsbruck, University Hospital of Internal Medicine IV
  • Innsbruck, Austria
    • Medical University Innsbruck, University Hospital of Internal Medicine I
  • Innsbruck, Austria
    • Medical University Innsbruck, University Hospital of Internal Medicine V
  • Klagenfurt, Austria
    • Klinikum Klagenfurt
  • Kufstein, Austria
    • Bezirkskrankenhaus Kufstein
  • Lienz, Austria
    • Klinikum Lienz
  • Sankt Johann In Tirol, Austria
    • Bezirkskrankenhaus St. Johann
  • Schwaz, Austria
    • Bezirkskrankenhaus Schwaz
  • Zams, Austria
    • Krankenhaus St. Vinzenz Zams
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Medical University Innsbruck, University Hospital of Internal Medicine III
• Germany
  • Aachen, Germany
    • University Hospital Aachen
  • Augsburg, Germany
    • University Hospital Augsburg
  • Bad Tölz, Germany
    • Asklepios Stadtklinik Bad Tölz
  • Dachau, Germany
    • Klinikum Dachau
  • Erlangen, Germany
    • University Hospital Erlangen
  • Essen, Germany
    • University Hospital Essen
  • Freiburg, Germany
    • University of Freiburg
  • Memmingen, Germany
    • Klinikum Memmingen
  • Munich, Germany
    • LMU Klinikum, Medizinische Klinik III
  • Munich, Germany
    • LMU Klinikum, Medizinische Klinik II
  • Munich, Germany
    • LMU Klinikum, Medizinische Klinik IV
  • Munich, Germany
    • München Klinik Bogenhausen und Schwabing
  • Munich, Germany
    • Rotkreuzklinikum Munich
  • Mühldorf, Germany
    • Krankenhaus Mühldorf
  • Rosenheim, Germany
    • Klinikum Rosenheim
  • Weiden, Germany
    • Krankenhaus Weiden
  • Bavaria
    • Munich, Bavaria, Germany, 81377
      • LMU Klinikum, Medizinische Klinik I

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Stopping/replacing ACEI/ARB; Chronic treatment with ACEI or ARB will be stopped or replaced.	Drug: ACE 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.
NO_INTERVENTION: Control; No intervention, which means further treatment with ACEI or ARB.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	30 days
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	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean of Sequential Organ Failure Assessment (SOFA) Score	minimum score is 0, maximum score is 24; higher score indicates poor outcome (death-adjusted)	30 days
Rates of Non-invasive Ventilation	Number of Participants with Non-invasive Ventilation	30 days
Rates of Renal Replacement Therapies		30 days
Number of Patients With Systolic/Diastolic Blood Pressure > 180/120 mmHg		30 days
Hospitalisation Due to Cardiac Decompensation	with causal relationship to stopping of ACEI/ARB therapy	30 days
Rates of Mechanical Ventilation		30 days

Collaborators and Investigators

• Sponsor: Medical University Innsbruck
• Collaborators: Ludwig-Maximilians - University of Munich; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)

Publications and helpful links

General Publications

• Bauer A, Schreinlechner M, Sappler N, Dolejsi T, Tilg H, Aulinger BA, Weiss G, Bellmann-Weiler R, Adolf C, Wolf D, Pirklbauer M, Graziadei I, Ganzer H, von Bary C, May AE, Woll E, von Scheidt W, Rassaf T, Duerschmied D, Brenner C, Kaab S, Metzler B, Joannidis M, Kain HU, Kaiser N, Schwinger R, Witzenbichler B, Alber H, Straube F, Hartmann N, Achenbach S, von Bergwelt-Baildon M, von Stulpnagel L, Schoenherr S, Forer L, Embacher-Aichhorn S, Mansmann U, Rizas KD, Massberg S; ACEI-COVID investigators. Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial. Lancet Respir Med. 2021 Aug;9(8):863-872. doi: 10.1016/S2213-2600(21)00214-9. Epub 2021 Jun 11. Erratum In: Lancet Respir Med. 2021 Aug 6;:

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 20, 2020
• Primary Completion (ACTUAL): February 16, 2021
• Study Completion (ACTUAL): February 24, 2021

Study Registration Dates

• First Submitted: April 14, 2020
• First Submitted That Met QC Criteria: April 16, 2020
• First Posted (ACTUAL): April 20, 2020

Study Record Updates

• Last Update Posted (ACTUAL): September 13, 2022
• Last Update Submitted That Met QC Criteria: August 18, 2022
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; angiotensin receptor blockers; ACE-inhibitors; RAS system
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists
• Other Study ID Numbers: EudraCT 2020-001206-35

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes