New Evidence Concerning Safety of ACE Inhibitors, ARBs in COVID-19

There continues to be a debate in the scientific community about the role that angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers play in coronavirus disease 2019 infection.

There continues to be a debate in the scientific community about the role that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) play in coronavirus disease 2019 (COVID-19) infection.

The issue revolves around the ACE-2 surface receptors in the lung, gut, and heart, which are the point of entry for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many years, the role of the ACE-2 receptor remained obscure until after the SARS-CoV-1 outbreak in 2002.

In 2003, a report in Nature detailed the role that the ACE-2 receptor served in allowing the virus to enter host cells. Since then, much has been learned about this receptor.1

Like all biological systems, an initial action causes a second action, which ultimately influences a biological process. In human systems, there are frequently counterregulatory or competing actions that balance the actions of stimulatory systems and inhibitory systems.

In the renin-angiotensin system, activation of renin occurs when there is a decrease in renal blood flow or a drop in sodium concentration. This triggers a series of enzymatic reactions mediated through the ACE-1 receptor to raise blood pressure, constrict blood vessels, and retain sodium.

The ACE-2 receptor, when stimulated, does the reverse. It causes vasodilation, excretion of sodium, retention of potassium, and a decrease in blood pressure. ACE inhibitors and ARBs, which are popular medications used to treat hypertension, heart failure, and renal disease, can raise ACE-2 levels.

There was a concern that more surface receptors in the lung would allow more of COVID-19 to enter cells or make the effect of the virus much worse. There is no proof of this, but it does make some sense.

An editorial in The Lancet early in the COVID-19 pandemic stated that physicians should stop the medications that work on the renin-angiotensin system.2

A media firestorm erupted, leading to the publication of a paper endorsed by all the leading cardiology journals in the United States and Europe to refute the editorial, urging physicians and patients not to stop their medications.3 Since then, potential therapies have been developed to either prevent the virus from attaching to the ACE-2 receptor, decreasing the amount of ACE-2 or increasing the level of ACE-2.

In one scenario, flooding the body with circulating ACE-2 might fool the virus into attaching to the circulating ACE-2 and not bind to surface receptors. In another scenario, decreasing ACE-2 levels would prevent the virus from entering a large number of cells, allowing natural immunity to kill the virus.

Since these receptors have multiple other functions, particularly in cardiovascular regulation, it is unclear to me whether they could cause more harm than good. Nothing done to human systems occurs in isolation, and changing a variable will influence other variables.

On April 22, 2020, it was reported in Circulation Research, that a large, well-designed study done in China showed that among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACE inhibitor/ARBs was associated with lower risk of all-cause mortality compared with ACE inhibitor/ARB nonusers during 28 days of follow-up. The results were significant using several methods of analysis.4

It was a significant study and hopefully will provide guidance for physicians and patients who take these medications.There is older research showing that ACE inhibitors were useful in treating other viral pneumonias.5

Talking to several intensive care physicians at Penn Medicine Princeton, I learned that patients with severe COVID-19 are routinely kept on these medications.



2. Lancet Respir Med. 2020; (published online March 11.) Muthiah Vaduganathan, M.D., M.P.H., Orly Vardeny, Pharm.D., Thomas Michel, M.D., Ph.D., John J.V. McMurray, M.D., Marc A. Pfeffer, M.D., Ph.D., and Scott D. Solomon, M.D.

3. Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19. Circ Res 2020;Apr 17:[Epub ahead of print].

4. Zhang P et al. Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134.

5. Henry C, Zaizafoun M, Stock E, Ghamande S, Arroliga AC, White HD. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proc (Bayl Univ Med Cent). 2018;31(4):419—423. Published 2018 Oct 26. doi:10.1080/08998280.2018.1499293