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

Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04467931
• Other study ID #: 00132408
• Status: Completed
• Start date: January 19, 2020
• Est. completion date: December 31, 2020

Study information

• Verified date: April 2021
• Source: University of Utah
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22213
• Est. completion date: December 31, 2020
• Est. primary completion date: October 21, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• COVID
• Hypertension

Intervention

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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	University of Utah	Salt Lake City	Utah

Sponsors (11)

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

Country where clinical trial is conducted

United States, 

References & 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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Negative control outcomes (Gastrointestinal bleed or urinary tract infection)	Time to first occurrence of gastrointestinal bleed or urinary tract infection. This will be a negative control outcome.	Through study completion (October 21, 2020).
Primary	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).
Primary	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	ICU admission	For aims 1 and 2, a secondary outcome will be time to intensive care unit (ICU) admission.	Through study completion (October 21, 2020).
Secondary	Mechanical ventilation	For aim 2, a secondary outcome will be time to mechanical ventilation.	Through study completion (October 21, 2020).
Secondary	Dialysis	For aim 2, a secondary outcome will be time to in-hospital dialysis.	Through study completion (October 21, 2020).