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

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.

• ACEI/ARB (Drug), also known as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan: 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 (Drug), 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: 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 (Drug), also known as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril: 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 (Drug), also known as azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan: 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.

Primary outcomes

• All-Cause-Hospitalization or All-Cause Mortality [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.
• All-Cause Mortality [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.

Secondary outcomes

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

Other outcomes

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

Sex: All, ages: 18 Years to any

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

• Results publication: 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

• Study Protocol and Statistical Analysis Plan (PDF, 2020-06-17)

• Adam P Bress, PharmD, MS, Principal investigator, University of Utah