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.
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.
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 Name: Array
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 Name: Array
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 Name: Array
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 Name: Array
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
University of Utah
Salt Lake City, Utah, United States
Adam P Bress, PharmD, MS, Principal Investigator
University of Utah