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

NCT04467931 | Completed FDA Drug

• 1 other identifier: 00132408
• Study Type: observational
• Target: 22,213
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hypertension; COVID

Keywords

angiotensin-converting enzyme inhibitor; angiotensin receptor antagonist; Veterans; antihypertensive medications

Outcome Measures

Primary Outcomes (2)

• All-Cause-Hospitalization or All-Cause Mortality

  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

  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 Outcomes (3)

• ICU admission

  Through study completion (October 21, 2020).

• Mechanical ventilation

  Through study completion (October 21, 2020).

• Dialysis

  Through study completion (October 21, 2020).

Other Outcomes (1)

• Negative control outcomes (Gastrointestinal bleed or urinary tract infection)

  Through study completion (October 21, 2020).

Study Arms (4)

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; Drug: Non-ACEI/ARB

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; Drug: ARB

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; Drug: Non-ACEI/ARB

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; Drug: ARB

Interventions

ACEI/ARB DRUG

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.

Also known as: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan

1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB; 2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB

Non-ACEI/ARB DRUG

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.

Also known as: doxazosin, prazosin, terazosin, acebutolol, nebivolol, atenolol, betaxolol, bisoprolol, metoprolol, pindolol, penbutolol, carvedilol, labetalol, nadolol, propranolol, timolol, amlodipine, felodipine, isradipine, nifedipine, nicardipine, nisoldipine, diltiazem, verapamil, clonidine, guanfacine, guanabenz, methyldopa, reserpine, hydralazine, minoxidil, aliskiren, spironolactone, eplerenone, bumetanide, furosemide, ethacrynic acid, torsemide, amiloride, triamterene, bendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone

1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB; 2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB

ACEI DRUG

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.

Also known as: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril

1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB; 2.2 COVID-19 Hospitalized, ACEI vs. ARB

ARB DRUG

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.

Also known as: azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan

1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB; 2.2 COVID-19 Hospitalized, ACEI vs. ARB

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• Derington CG, Cohen JB, Mohanty AF, Greene TH, Cook J, Ying J, Wei G, Herrick JS, Stevens VW, Jones BE, Wang L, Zheutlin AR, South AM, Hanff TC, Smith SM, Cooper-DeHoff RM, King JB, Alexander GC, Berlowitz DR, Ahmad FS, Penrod MJ, Hess R, Conroy MB, Fang JC, Rubin MA, Beddhu S, Cheung AK, Xian W, Weintraub WS, Bress AP. Angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use and COVID-19-related outcomes among US Veterans. PLoS One. 2021 Apr 23;16(4):e0248080. doi: 10.1371/journal.pone.0248080. eCollection 2021.

  PMID: 33891615 RESULT

MeSH Terms

Conditions

Hypertension

Interventions

benazepril; Captopril; Enalapril; Fosinopril; Lisinopril; moexipril; Perindopril; Quinapril; Ramipril; trandolapril; azilsartan; candesartan; eprosartan; Irbesartan; Losartan; olmesartan; Telmisartan; Valsartan; Doxazosin; Prazosin; Terazosin; Acebutolol; Nebivolol; Atenolol; Betaxolol; Bisoprolol; Metoprolol; Pindolol; Penbutolol; Carvedilol; Labetalol; Nadolol; Propranolol; Timolol; Amlodipine; Felodipine; Isradipine; Nifedipine; Nicardipine; Nisoldipine; Diltiazem; Verapamil; Clonidine; Guanfacine; Guanabenz; Methyldopa; Reserpine; Hydralazine; Minoxidil; aliskiren; Spironolactone; Eplerenone; Bumetanide; Furosemide; Ethacrynic Acid; Torsemide; Amiloride; Triamterene; Bendroflumethiazide; Chlorothiazide; Chlorthalidone; Hydrochlorothiazide; Indapamide; Metolazone

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Proline; Imino Acids; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Dipeptides; Oligopeptides; Peptides; Phosphinic Acids; Organophosphorus Compounds; Organic Chemicals; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Tetrahydroisoquinolines; Isoquinolines; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Spiro Compounds; Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Polycyclic Compounds; Imidazoles; Benzimidazoles; Valine; Amino Acids, Branched-Chain; Amino Acids, Essential; Quinazolines; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines; Ethanolamines; Benzopyrans; Pyrans; Carbazoles; Heterocyclic Compounds, 3-Ring; Salicylamides; Amides; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Thiadiazoles; Thiazoles; Sulfur Compounds; Morpholines; Oxazines; Dihydropyridines; Pyridines; Benzazepines; Phenethylamines; Ethylamines; Imidazolines; Guanidines; Amidines; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Dihydroxyphenylalanine; Catecholamines; Catechols; Phenols; Phenylalanine; Amino Acids, Aromatic; Tyrosine; Yohimbine; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indolizidines; Indolizines; Phthalazines; Pyridazines; Piperidines; Pyrimidines; Lactones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Sulfonamides; meta-Aminobenzoates; Aminobenzoates; Benzoates; Sulfones; Sulfanilamides; Aniline Compounds; Phenoxyacetates; Glycolates; Acetates; Acids, Acyclic; Hydroxy Acids; Pyrazines; Pteridines; Benzothiadiazines; Thiazides; Benzenesulfonamides; Benzophenones; Phthalimides; Imides; Ketones; Isoindoles; Quinazolinones

Study Officials

• Adam P Bress, PharmD, MS

  University of Utah

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 6, 2020
• First Posted: July 13, 2020
• Study Start: January 19, 2020
• Primary Completion: October 21, 2020
• Study Completion: December 31, 2020
• Last Updated: April 28, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)