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.