Introduction
Soon after the report of first clusters of COVID-19 cases in China in
December 2019, concerns were raised among clinicians and investigators
that angiotensin-converting enzyme inhibitors (ACEIs) and
angiotensin-receptor blockers (ARBs) might increase susceptibility to
COVID-19 infection and the likelihood of severe and fatal COVID-19
illness (1). These concerns are based on the concept that
angiotensin-converting enzyme 2 (ACE2), an enzyme potentially
up-regulated by ACEIs/ARBs use, is the viral entry receptor that
COVID-19 uses to enter lung cell (2), coupled with the observation of
high prevalence of hypertension and other cardiovascular comorbidities
among COVID-19 patients who have poor outcomes (3) . Consequently, it
was speculated that due to considerable prescribing of ACEIs/ARBs to
treat cardiovascular diseases (CVD), this would adversely affect
outcomes from COVID-19 (4) with underlying cardiac and kidney diseases
already associated with poorer outcomes (3, 5, 6). Consequently, care to
avoid treatments that well add to this.
Unsurprisingly, discussions regarding the potential impact of ACEIs/
ARBs has resulted in anxiety, which might cause patients and clinicians
to discontinue or stop these medications (7) . This should be avoided as
there will be harm from the indiscriminate withdrawal of ACEIs/ARBs (8).
This concern is complicated by uncertainty surrounding the up-regulation
of ACE2 by ACEIs/ARBs (9). Furthermore, the paradoxical protective role
of ACEIs/ARBs in COVID-19 patients is also being proposed (10). Due to
these controversial findings, and despite consistent and reassuring
recommendations for the continued use of ACEIs/ARBs in COVID-19 patients
issued by International Societies (11), these concerns remain. We wish
to address this as we have already seen the impact that inappropriate
endorsement of treatments can have on morbidity and mortality. Early
endorsement of hydroxychloroquine resulted in drug shortages for other
indications, price hikes, increased adverse drug reactions and deaths
from suicides (12, 13). However, subsequent studies failed to show
clinical benefit resulting in the World Health Organisation (WHO) and
the National Institute of Health (NIH) in the USA stopping the
hydroxychloroquine arm in their studies (14-16). A similar situation has
been seen with lopinavir/ritonavir(15). Consequently it is imperative
that any considerations regarding management are evidenced based.
We are aware that several observational studies have been conducted to
address these concerns. However, these studies have reported conflicting
findings which is a concern given the controversies with
hydroxychloroquine and lopinavir/ritonavir. For instance, some studies
(17-22) have reported a lower risk of severe COVID-19 outcomes with
ACEIs/ARBs whilst another study (23) found a higher risk. Similarly,
ACEIs/ARBs have been associated with lower mortality rates in some
studies (17, 20, 24-27) whilst others (23, 28) reported higher mortality
rates. We are also aware that two recently published systematic reviews
(29, 30) containing 16 studies reported no evidence of any association
between ACEIs/ARBs and mortality, severe COVID-19 outcomes, or acquiring
COVID-19 infection; however, these studies only analysed a limited range
of outcomes, and did not report the effects of ACEIs and ARBs
individually. The authors also did not undertake any sub-group analysis
to explore the effect of potential confounders such as study’s quality
and there are concerns that the findings may now be out-dated.
Furthermore, one of these studies (30) only used narrative synthesis of
the data. Consequently, we sought to undertake an updated and
comprehensive evaluation of effect of ACEIs/ARBs use on all reported
COVID-19 related outcomes, including exploration of any class
differences, through a systematic review of the literature coupled with
a meta-analysis.