Message for the clinic:
There is no indication from present evidence to withhold or withdraw ACEi/ARB in patients with SARS-CoV-2.
1.0 Introduction
Coronavirus disease 2019 (COVID-19) is a rapidly unravelling pandemic infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). It is highly infectious, with a case fatality rate of 1% to 5% (1). Despite a wide variability in the prevalence and case fatality rates in the published case-series of COVID-19 from China and USA, it is now clear that patients with underlying pulmonary disease, cardiac disease, hypertension, diabetes mellitus (DM), and renal disease are not only more likely to contract SARS-CoV2 but also have higher morbidity and mortality rates (2, 3, 4). Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are commonly used in patients with cardiac diseases, hypertension, many renal conditions, and DM, which directed attention towards the role of ACEi/ARBs in COVID-19, more so because SARS-CoV2 uses angiotensin-converting enzyme 2 (ACE2) as a co-receptor to enter cells (5).
ACE2, a homologue of angiotensin-converting enzyme 1 (ACE1), cleaves angiotensin II (Ang II), the main active peptide of the renin-angiotensin-aldosterone system (RAAS), to form angiotensin-(1-7) (6, 7). Angiotensin-(1-7) acts as a counter-regulatory peptide by attenuating the deleterious effects of angiotensin II, namely vasoconstriction, sodium retention and fibrosis. ACE2 is a transmembrane protein that is anchored to the apical surface of the cell. It can be cleaved and released into the circulation. ACE2 is expressed in the heart (cardiomyocytes, cardiac fibroblasts, coronary endothelial cells), kidney, testis, gastrointestinal system and type II alveolar cells in the lung (8).
Some, but not all, animal studies have shown that ACEi/ARBs upregulate ACE2 expression (9). This has led to the speculation that use of ACEi/ARB shall not only increase the risk but also the severity of SARS-CoV2 infection. However, unlike in animal models, in the few available human studies, the effects of RAAS inhibitors on ACE2 is far from clear (10, 11). Moreover, animal, and some human, studies have failed to establish the effects of ACEi or ARB on the expression of ACE2 in alveolar cells in the lung.
In contrast to the speculative detrimental effect of upregulation of ACE2 expression in COVID-19, elevated ACE2 levels has a number of beneficial effects. The conversion of Ang II to Ang-(1-7) ameliorates the harmful effects of Ang II, and instead mediates vasodilation and anti-inflammatory effects. Animal studies have suggested that downregulation of ACE2 may result in unopposed action of angiotensin II, that can mediate acute lung injury in viral infections (12), including SARS-CoV2 (13), which can be ameliorated by recombinant ACE2 (14) or RAAS blockade (15). Moreover, animal studies have demonstrated the protective effect of ACE2 on the myocardium (16).
This postulated dual role of ACEi/ARBs, based mostly on theoretical concerns and animal data, has created a dilemma for clinicians because many patients with co-morbidities like diabetes, hypertension, coronary artery disease and chronic kidney disease that increase susceptibility to, and a poor outcome in, SARS-Cov-2 infection, are on ACEi and ARBs. More evidence from the laboratory, and the clinics, are urgently needed to guide frontline physicians during this rapidly progressive pandemic with potential to cause massive devastation. Among these, retrospective analyses of outcomes in patients with COVID-19 who were on ACEi/ARBs can serve as a good evidence base. However, such analyses are limited at present due to very few retrospective case studies with outcomes in patients with SARS-CoV2 infection on ACEi/ARBs (17, 18, 19, 20, 21, 22); moreover, the number of patients included, and the number of outcomes of interest, are small in these individual studies to draw any meaningful conclusions. We therefore did a meta-analysis of the studies reported till 21.04.2020 on the outcomes in patients with COVID-19 on ACEi/ARBs to strengthen the evidence base by determining the benefit-risk ratio of these medications in patients with COVID-19.