Renin–angiotensin system blockade in the COVID-19 pandemic

Abstract

In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin-angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counter-regulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.

Antibodies Against Angiotensin II Receptor Type 1 and Endothelin A Receptor Are Associated With an Unfavorable COVID19 Disease Course

“…Similarly, the agonistic effect of anti-ETAR1 antibodies could potentially be mitigated by the use of endothelin receptor agonists such as the ETAR-selective antagonist ambrisentan or the dual ETAR and ETBR antagonist bosentan (12). In a series of recent studies, however, the use of ACEI and ARBs has, on balance, not been found to be unequivocally associated with severity of disease (18). This type of observational research is hampered by confounding factors and bias, however, and whether any of these treatments have a positive effect on the outcome of COVID-19 pneumonia remains to be definitively determined and requires further study.…”

Final results of BIRCOV trial (ARB, ACEI, DRi in COVID-19)

“…A double block of ACE inhibitors and ARB (the SARS-CoV-2) is accompanied by the largest blood pressure decrease, a double block of DRi and ARB (the SARS-CoV-2) is characterized by a smaller decrease in pressure, and a double block of ARB + ARB (the SARS-CoV-2) has practically no effect on blood pressure. This is associated with a trend that increases the risk of death in people with COVID-19 who are taking ARB as an antihypertensive agent [15]. Jordana B. Cohen et al (2021) presented three possible mechanisms of the effect of RAS inhibitors, one of which, in our opinion, was shown in the results of the BIRKOV study [15].…”

Kidney implications of SARS-CoV2 infection in children

“…When it was discovered that ACE2 served as the primary cellular entry point for SARS-CoV2, researchers rushed to determine the implications for patients with hypertension and particularly those who routinely take ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs). There remain mixed results with some studies suggesting a protective effect for those taking ACEi/ARBs as they may competitively inhibit the receptors, while others showing a deleterious effect from higher rates of AKI and admissions to critical care units and electrolyte derangements [ 66 , 67 ]. A meta-analysis among adult patients with hypertension and COVID-19 revealed lower mortality among those who were on ACEi/ARBs compared to those not on the medications [ 68 ].…”