ACEI or ARB and COVID-19 Severity and Mortality in US Veterans

April 26, 2021 updated by: Adam Bress, University of Utah

Association Between Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use and COVID-19 Severity and Mortality Among US Veterans

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, enters type II pneumocytes using angiotensin-converting enzyme 2 (ACE2). It is unclear whether ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) increase, decrease, or have no significant effect on ACE2 expression or activity. Therefore, ACEI and ARB may be harmful, beneficial, or have no impact on Coronavirus Disease 2019 severity and mortality. The Specific Aims of this observational study are: (1) Among SARS-CoV-2-positive outpatients, compare all-cause hospitalization and mortality rates between: 1.1 Current users of a range of doses of ACEI/ARB- vs. non- ACEI/ARB-based regimens, and 1.2 Current users of a range of doses of ACEI- vs. ARB-based regimens, and (2) Among those hospitalized for COVID-19, compare all-cause mortality between: 2.1 Current users of a range of doses of ACEI/ARB- vs. non- ACEI/ARB-based regimens, and 2.2 Current users of a range of doses of ACEI- vs. ARB-based regimens.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The Coronavirus Disease 2019 (COVID-19) pandemic has killed >129,000 Americans as of June 30, 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, enters type II pneumocytes using angiotensin-converting enzyme 2 (ACE2). ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase ACE2 expression. Theoretically, if ACEI/ARB use increases ACE2 expression in the lungs, ACEI/ARBs could promote SARS-CoV-2 entry into type II pneumocytes and worsen COVID-19 infection. In contrast, other evidence suggests that ACEI/ARBs may mitigate virus-induced inflammatory responses in the lungs by upregulating ACE2-mediated generation of the vasodilator and anti-inflammatory protein angiotensin-(1-7), thereby preventing tissue damage. Few data exist on the direction or magnitude of the association between ACEI/ARB use and COVID-19 severity, and whether these associations differ between ACEIs and ARBs. Because ACEI/ARBs are among the most commonly used prescription medications, it is critical to determine if ACEI/ARB users have a differential risk of more severe COVID-19 infection compared to non-users. The objective of this study is to reduce morbidity and mortality of the COVID-19 pandemic by generating timely evidence on the direction and magnitude of the association between ACEI/ARB use and COVID-19 severity and mortality.

Study Type

Observational

Enrollment (Actual)

22213

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • University of Utah

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Aim 1: Positive test for SARS-CoV-2 in the outpatient setting, diagnosed with hypertension prior to the index date, and be treated with an antihypertensive in the 90 days prior to the index date.

Aim 2: Hospitalized for COVID-19, diagnosed with hypertension prior to the index date, and be treated with an antihypertensive in the 90 days prior to the index date.

ACEI/ARB vs. non-ACEI/ARB analyses (aims 1.1 and 2.1): Do not have compelling indications that would warrant preferential treatment with an ACEI or an ARB (i.e., diabetes, stroke, chronic kidney disease, heart failure with reduced ejection fraction, or coronary heart disease).

ACEI vs. ARB analyses (aims 1.2 and 2.2): Not concomitantly treated with an ACEI and an ARB in the 90 days prior to the index date, and must be treated with at least an ACEI or an ARB in the 90 days prior to the index date.

Description

Inclusion Criteria:

  • Positive SARS-CoV-2 test in the outpatient setting (Aim 1) or hospitalized for COVID-19 (Aim 2)
  • Meet continuous enrollment criteria (≥1 inpatient or any outpatient encounter in each of the two, six-month periods during the 365 days prior to the index date)
  • Do not have data inconsistencies (test patients, not Veterans, multiple death dates in data, or not alive on index date)
  • Diagnosed with hypertension at any point prior to the index date
  • Had at least one prescription dispensed for an antihypertensive medication in the 90 days prior to the index date

Exclusion Criteria:

  • Aim 1.1 and 2.1 (ACEI/ARB vs. non-ACEI/ARB comparison): diagnosed with a compelling indication for ACEI/ARB at any point prior to the index date (i.e., diabetes, stroke, chronic kidney disease, heart failure with reduced ejection fraction, or coronary heart disease)
  • Aim 1.2 and 2.2 (ACE vs. ARB comparison): prescription fills for both an ACEI and an ARB in the 90 days prior to the index date; no prescription fill for an ACEI or an ARB in the 90 days prior to the index date

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB
Among Veterans with treated hypertension and without compelling indications who test positive for SARS-CoV-2, compare all-cause hospitalization and all-cause mortality rates between current users of a range of doses of ACEI/ARB- vs. non-ACEI/ARB-based regimens.
Drug: ACEI/ARB
Veterans will be categorized as exposed to ACEI/ARB if they have one or more pharmacy fills for an oral ACEI or an ARB in the 90 days (± 14 days) prior to each Veteran's index date. Sacubitril/valsartan (Brand name: Entresto®) will be excluded from ARB exposures.
Other Names:
  • losartan
  • azilsartan
  • candesartan
  • eprosartan
  • telmisartan
  • valsartan
  • benazepril
  • captopril
  • enalapril
  • fosinopril
  • lisinopril
  • moexipril
  • perindopril
  • quinapril
  • ramipril
  • trandolapril
  • irbesartan
  • olmesartan
Drug: Non-ACEI/ARB
Veterans will be categorized as exposed to a non-ACEI/ARB if they have one or more pharmacy fills for an oral non-ACEI or ARB medication in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an ACEI/ARB medication in the 90 days (± 14 days) prior to each Veteran's index date. Specific drug classes include: aldosterone receptor antagonist, beta-blocker, calcium channel blocker, centrally-acting drug, direct arterial vasodilator, direct renin inhibitor, thiazide diuretic, loop diuretic, and potassium sparing diuretic.
Other Names:
  • amlodipine
  • nicardipine
  • furosemide
  • spironolactone
  • eplerenone
  • hydrochlorothiazide
  • bumetanide
  • prazosin
  • propranolol
  • labetalol
  • nifedipine
  • reserpine
  • hydralazine
  • nebivolol
  • metoprolol
  • doxazosin
  • terazosin
  • acebutolol
  • atenolol
  • betaxolol
  • bisoprolol
  • pindolol
  • penbutolol
  • carvedilol
  • nadolol
  • timolol
  • felodipine
  • isradipine
  • nisoldipine
  • diltiazem
  • verapamil
  • clonidine
  • guanfacine
  • guanabenz
  • methyldopa
  • minoxidil
  • aliskiren
  • ethacrynic acid
  • torsemide
  • amiloride
  • triamterene
  • bendroflumethiazide
  • chlorothiazide
  • chlorthalidone
  • indapamide
  • metolazone
1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB
Among Veterans with treated hypertension who test positive for SARS-CoV-2, compare all-cause hospitalization and all-cause mortality rates between current users of a range of doses of ACEI- vs. ARB-based regimens.
Drug: ACEI
Veterans will be categorized as exposed to an ACEI if they have one or more pharmacy fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an oral ARB in the 90 days (± 14 days) prior to each Veteran's index date.
Other Names:
  • benazepril
  • captopril
  • enalapril
  • fosinopril
  • lisinopril
  • moexipril
  • perindopril
  • quinapril
  • ramipril
  • trandolapril
Drug: ARB
Veterans will be categorized as exposed to an ARB if they have one or more pharmacy fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date. Sacubitril/valsartan (Brand name: Entresto®) will be excluded from ARB exposures.
Other Names:
  • losartan
  • azilsartan
  • candesartan
  • eprosartan
  • telmisartan
  • valsartan
  • irbesartan
  • olmesartan
2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB
Among Veterans with treated hypertension and without compelling indications who are hospitalized for COVID-19, compare all-cause mortality rates between current users of a range of doses of ACEI/ARB- vs. non-ACEI/ARB-based regimens.
Drug: ACEI/ARB
Veterans will be categorized as exposed to ACEI/ARB if they have one or more pharmacy fills for an oral ACEI or an ARB in the 90 days (± 14 days) prior to each Veteran's index date. Sacubitril/valsartan (Brand name: Entresto®) will be excluded from ARB exposures.
Other Names:
  • losartan
  • azilsartan
  • candesartan
  • eprosartan
  • telmisartan
  • valsartan
  • benazepril
  • captopril
  • enalapril
  • fosinopril
  • lisinopril
  • moexipril
  • perindopril
  • quinapril
  • ramipril
  • trandolapril
  • irbesartan
  • olmesartan
Drug: Non-ACEI/ARB
Veterans will be categorized as exposed to a non-ACEI/ARB if they have one or more pharmacy fills for an oral non-ACEI or ARB medication in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an ACEI/ARB medication in the 90 days (± 14 days) prior to each Veteran's index date. Specific drug classes include: aldosterone receptor antagonist, beta-blocker, calcium channel blocker, centrally-acting drug, direct arterial vasodilator, direct renin inhibitor, thiazide diuretic, loop diuretic, and potassium sparing diuretic.
Other Names:
  • amlodipine
  • nicardipine
  • furosemide
  • spironolactone
  • eplerenone
  • hydrochlorothiazide
  • bumetanide
  • prazosin
  • propranolol
  • labetalol
  • nifedipine
  • reserpine
  • hydralazine
  • nebivolol
  • metoprolol
  • doxazosin
  • terazosin
  • acebutolol
  • atenolol
  • betaxolol
  • bisoprolol
  • pindolol
  • penbutolol
  • carvedilol
  • nadolol
  • timolol
  • felodipine
  • isradipine
  • nisoldipine
  • diltiazem
  • verapamil
  • clonidine
  • guanfacine
  • guanabenz
  • methyldopa
  • minoxidil
  • aliskiren
  • ethacrynic acid
  • torsemide
  • amiloride
  • triamterene
  • bendroflumethiazide
  • chlorothiazide
  • chlorthalidone
  • indapamide
  • metolazone
2.2 COVID-19 Hospitalized, ACEI vs. ARB
Among Veterans with treated hypertension who are hospitalized for COVID-19, compare all-cause mortality rates between current users of a range of doses of ACEI- vs. ARB-based regimens.
Drug: ACEI
Veterans will be categorized as exposed to an ACEI if they have one or more pharmacy fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an oral ARB in the 90 days (± 14 days) prior to each Veteran's index date.
Other Names:
  • benazepril
  • captopril
  • enalapril
  • fosinopril
  • lisinopril
  • moexipril
  • perindopril
  • quinapril
  • ramipril
  • trandolapril
Drug: ARB
Veterans will be categorized as exposed to an ARB if they have one or more pharmacy fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date. Sacubitril/valsartan (Brand name: Entresto®) will be excluded from ARB exposures.
Other Names:
  • losartan
  • azilsartan
  • candesartan
  • eprosartan
  • telmisartan
  • valsartan
  • irbesartan
  • olmesartan

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All-Cause-Hospitalization or All-Cause Mortality
Time Frame: Through study completion (October 21, 2020).
For outpatient Veterans with a positive SARS-CoV-2 test (Aims 1.1 and 1.2), the primary outcome is a composite of time to all-cause hospitalization or all-cause mortality.
Through study completion (October 21, 2020).
All-Cause Mortality
Time Frame: Through study completion (October 21, 2020).
For Veterans hospitalized with COVID-19 (Aims 2.1 and 2.2), the primary outcome is time to all-cause mortality.
Through study completion (October 21, 2020).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
ICU admission
Time Frame: Through study completion (October 21, 2020).
For aims 1 and 2, a secondary outcome will be time to intensive care unit (ICU) admission.
Through study completion (October 21, 2020).
Mechanical ventilation
Time Frame: Through study completion (October 21, 2020).
For aim 2, a secondary outcome will be time to mechanical ventilation.
Through study completion (October 21, 2020).
Dialysis
Time Frame: Through study completion (October 21, 2020).
For aim 2, a secondary outcome will be time to in-hospital dialysis.
Through study completion (October 21, 2020).

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Negative control outcomes (Gastrointestinal bleed or urinary tract infection)
Time Frame: Through study completion (October 21, 2020).
Time to first occurrence of gastrointestinal bleed or urinary tract infection. This will be a negative control outcome.
Through study completion (October 21, 2020).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Utah

Collaborators

Boston University
University of Pennsylvania
Northwestern University
Columbia University
Johns Hopkins Bloomberg School of Public Health
University of Florida
Wake Forest University Health Sciences
Edith Nourse Rogers Memorial Veterans Hospital
VA Salt Lake City Health Care System
MedStar Georgetown University Hospital

Investigators

  • Principal Investigator: Adam P Bress, PharmD, MS, University of Utah

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 19, 2020

Primary Completion (Actual)

October 21, 2020

Study Completion (Actual)

December 31, 2020

Study Registration Dates

First Submitted

July 6, 2020

First Submitted That Met QC Criteria

July 9, 2020

First Posted (Actual)

July 13, 2020

Study Record Updates

Last Update Posted (Actual)

April 28, 2021

Last Update Submitted That Met QC Criteria

April 26, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 00132408

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

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.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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