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

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

Sponsors

Lead Sponsor: University of Utah

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

Source University of Utah
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.

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.

Overall Status Active, not recruiting
Start Date January 19, 2020
Completion Date July 31, 2020
Primary Completion Date July 31, 2020
Study Type Observational
Primary Outcome
Measure Time Frame
All-Cause-Hospitalization or All-Cause Mortality Through study completion (approximately July 31, 2020).
All-Cause Mortality Through study completion (approximately July 31, 2020).
Secondary Outcome
Measure Time Frame
ICU admission Through study completion (approximately July 31, 2020).
Duration of hospitalization Through study completion (approximately July 31, 2020).
Mechanical ventilation Through study completion (approximately July 31, 2020).
Dialysis Through study completion (approximately July 31, 2020).
Enrollment 10000
Condition
Intervention

Intervention Type: Drug

Intervention Name: ACEI/ARB

Description: 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.

Intervention Type: Drug

Intervention Name: Non-ACEI/ARB

Description: 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.

Intervention Type: Drug

Intervention Name: ACEI

Description: 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.

Intervention Type: Drug

Intervention Name: ARB

Description: 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.

Eligibility

Sampling Method: Non-Probability Sample

Criteria:

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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Adam P Bress, PharmD, MS Principal Investigator University of Utah
Location
Facility: University of Utah
Location Countries

United States

Verification Date

July 2020

Responsible Party

Type: Principal Investigator

Investigator Affiliation: University of Utah

Investigator Full Name: Adam Bress

Investigator Title: Associate Professor

Keywords
Has Expanded Access No
Condition Browse
Arm Group

Label: 1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB

Description: 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.

Label: 1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB

Description: 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.

Label: 2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB

Description: 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.

Label: 2.2 COVID-19 Hospitalized, ACEI vs. ARB

Description: 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.

Patient Data No
Study Design Info

Observational Model: Cohort

Time Perspective: Retrospective

Source: ClinicalTrials.gov