RAS-Blocking Agents in Patients With COVID-19: What Have We Learned?
Michael J. Bloch, MD
Associate Professor, University of Nevada School of Medicine
Medical Director, Renown Vascular Care, Renown Institute for Heart and Vascular Health
President, Blue Spruce Medical Consultants, PLLC
Bloch MJ. RAS-blocking agents in patients with COVID-19: what have we learned? Consultant360. Published online: January 26, 2021.
Based on work with SARS-CoV-1 and Middle East respiratory syndrome (MERS), early in the pandemic we all learned that the SARS-CoV-2 virus enters cells through interaction with tissue-bound angiotensin-converting enzyme 2 (ACE2) receptors. Like its better-known relative, the ACE receptor, ACE2 is an integral part of the renin-angiotensin system (RAS). ACE2 is primarily responsible for degrading angiotensin II which increases vasoconstriction, cytotoxicity, and inflammation, to angiotensin 1-7, which increases vasodilation, decreases inflammation, and promotes beneficial tissue remodeling.
With this understanding, clinicians have been faced with the dilemma of whether or not to continue RAS-blocking agents in patients with COVID-19 infection. There is some theoretical concern that use of ACE inhibitors and angiotensin receptor blockers (ARBs) could lead to upregulation of ACE2 and more potential opportunities for SARS-CoV-2 to enter cells, increasing the risk and severity of infection. Luckily, we now have a series of observational studies that have shown no increase in mortality or other signs of severe illness in hospitalized patients with COVID-19 taking ACE inhibitors or ARBs, compared with either those taking other antihypertensive agents or no blood pressure medications at all.1-4
In fact, there is now an emerging theory that, perhaps, RAS-blocking agents may actually be beneficial for patients with COVID-19. It appears that SARS-CoV-2 infection may actually decrease the amount of ACE2 available on tissue surfaces. With less ACE2 available, there is an increase in the relative effect of angiotensin II, compared with angiotensin 1-7, favoring vasoconstriction, cytotoxicity, and inflammation. According to this hypothesis, use of RAS-blocking agents—which in the case of ACE inhibitors, decrease angiotensin II levels, and in the case of ARBs, decrease the binding of angiotensin II to the angiotensin 1 receptor—could actually be beneficial in restoring the balance of angiotensin II and angiotensin 1-7 in the setting of COVID-19 infection.
While the observational data cited above demonstrates no apparent harm from RAS-blocking agents in hospitalized patients with COVID-19, these studies may be subject to important confounding variables, particularly since we know that patients with heart disease and hypertension tend to have worse outcomes with COVID-19. Clearly, prospective randomized controlled trials are needed to determine the net clinical benefit or harm of RAS-blocking agents in COVID-19 infection. Although none have yet been completed or reported, a number of studies with ARBs are ongoing or planned in both hospitalized and nonhospitalized patients with COVID-19.5
Pending the publication of randomized controlled clinical trials, based on the available evidence to date, the Heart Failure Society of America/American College of Cardiology/American Heart Association statement remains as valid today as when it was published in the early stages of the pandemic: “Continuation of RAS antagonists for those patients who are currently prescribed such agents for indications for which these agents are known to be beneficial, such as heart failure, hypertension, or ischemic heart disease.”6 Future studies will not only help determine whether or not this statement should be revised but will also help us gain a more complete understanding and appreciation of the role that ACE2 plays in cardiovascular health and disease.
- Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-angiotensin-aldosterone system blocker and the risk of Covid-19. N Engl J Med. 2020;382:2431-2440. doi:10.1056/NEJMoa2006923
- Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of covid-19 patients with hypertension. Emerg Microbes Infect. 2020;9(1):757-760. https://doi.org/10.1080/22221751.2020.1746200
- Reynold HR, Adhikari S, Pulgarin C, et al. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19. N Engl J Med. 2020;382(25):2441-2448. https://doi.org/10.1056/nejmoa2008975
- Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA. 2020;323(20):2052-2059. https://doi.org/10.1001/jama.2020.6775
- Bloch MJ. Renin-angiotensin system blockade in COVID-19: good, bad or indifferent. J Am Col Cardiol. 2020;78(3):277-279. https://doi.org/10.1016/j.jacc.2020.06.003.
- Bozkurt B, Kovacs R, Harrington B. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. American College of Cardiology. Published online: March 17, 2020. Accessed: January 25, 2021. https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19