4.0 Discussion:
Speculation over the deleterious effects of ACEi/ARB in patients with
COVID-19 stems from the fact that SARS-CoV-2 uses the ACE2 receptor to
enter target human cells (5). A few preclinical studies have suggested
that RAAS inhibitors increase ACE2 expression, raising concerns
regarding their safety in patients with COVID-19 (9). This thought was
seemingly further strengthened by a retrospective study on hospitalised
patients with COVID-19 in Wuhan, China, which reported that hypertensive
patients on ACEi/ARB had an increased tendency to develop severe
pneumonia with SARS COV 2 infection compared to those not on ACEi/ARB
(54% vs. 32% respectively; p = 0.055) (17). This created confusion
amongst patients and their health care workers since ACEi/ARB are an
essential component of treatment not only in many individuals with
hypertension but also in those with diabetes, coronary artery disease,
heart failure and chronic kidney disease; sudden withdrawal of these
medications in these patients might cause harm (22). However, findings
from the same study showed that hypertensive patients with COVID-19 who
were on ACEi/ARB had lesser hospitalisation (18% vs. 28%), lesser
number of deaths (7% vs. 11%), and a higher number of discharges (75%
vs. 61%) when compared to those not on ACEi/ARB; however, these
observations failed to reach statistical significance due to the small
number of patients analysed (17). In another study from China on elderly
hypertensive patients with COVID-19, treatment with ARB was associated
with a significant reduction in the risk of disease severity (OR=0·343,
95% CI 0·128-0·916, p=0·025) (18). A study by Yang et al. reported that
compared to patients on non-ACEi/ARB antihypertensives, those on
ACEi/ARB had a significant reduction in inflammatory markers, namely
C-reactive protein (11.5 [ACEi/ARB] [4.0-58.2] vs. 33.9
[non ACEi/ARB] [5.1-119.2]; p=0.049) and procalcitonin (0.061
[ACEi/ARB] [0.044-0.131] vs. 0.121 [non ACEi/ARB]
[0.052-0.295]; p=0.008), (19) consistent with previously described
anti-inflammatory properties of ACEi/ARB (23, 24). This study also
revealed a much lower proportion of critical patients (9.3% vs.22.9%; p=0.061), and a lower death rate (4.7% vs. 13.3%;
p=0.216) in those receiving ACEi/ARB compared to those not on ACEi/ARB;
however, these differences failed to reach statistical significance
(19).
In a study from the United Kingdom, Bean et al. reported that in
patients with COVID-19, those treated with ACEi had a lower rate of
death or transfer to a critical care unit [OR 0.29 CI 0.10-0.75 p
<0.01], after adjusting for age, gender, and comorbidities
(hypertension, diabetes mellitus, ischaemic heart disease and heart
failure) compared to those who were not on ACEi/ARB (20). Recently,
Zhang et al. reported a large multicentre retrospective study on 1128
hospitalised hypertensive patients with COVID-19; there was a
significant reduction in all-cause mortality (adjusted HR, 0.30; 95%CI,
0.12-0.70; P = 0.01) in patients treated with ACEi/ARB compared to those
treated with other anti-hypertensive medications, even after adjusting
for a large number of variables (21). This study also demonstrated that
use of ACEi/ARB was associated with lower risk of septic shock when
compared to those not on ACEi/ARB (adjusted HR, 0.36; 95% CI,
0.16-0.84; P = 0.01) (21).
In a recently published retrospective analysis of hypertensive patients
from China, Li J et al. have reported that there was no difference in
severity of disease (32.9% vs 30.7%; P = 0.645) or mortality (27.3%vs
33.0%; P = 0.34) among the hypertensive patients on ACEIs/ARBs when
compared to those who were not on ACEi/ARB. (22)
The six studies described above, which have individually reported on the
effect of ACEi/ARB in patients with COVID-19, are limited by the small
number of patients and varied outcomes reported that makes it difficult
to ascertain the effect of ACEi/ARB in patients with COVID-19. Ours is
the first meta-analysis reporting the effect of ACEi/ARB on death and
severity of disease in patients with COVID-19. We noted that patients
with COVID-19 who were on ACEi/ARB had a 38% non-significant reduction
in the odds for risk of developing severe disease [OR 0.62 (95% CI:
0.31-1.23), I2=70.36] when compared to those not on
ACEi/ARB. The odds for risk of hospitalisation was also reduced by 19%
(95% CI: 0.42-1.55, I2: 0.000) among patients with
COVID-19 on ACEi/ARB compared to those not on ACEi/ARB, which failed to
reach statistical significance. Most importantly, our meta-analysis of
the four studies that have reported on death, reveals a statistically
significant 43% reduction [OR 0.57 (95% CI: 0.37-0.88,
I2=0.000) p=0.01] in the odds of death among
patients with COVID-19 on ACEi/ARB compared to those not on ACEi/ARB,
with negligible heterogeneity of data. The statistically significant
benefits seen in our meta-analysis in the odds of death with use of
ACEi/ARB in patients with
COVID-19, together with a trend in
reduction of severity of disease and risk for hospitalization,
strengthens the recommendations from European Societies of Cardiology
(25), Heart Failure Society of America, American College of Cardiology,
American Heart Association (26) and International Society of
Hypertension (27) to continue ACEi/ARB in patients with COVID-19. The
reduction in the odds of death and the trend in the risk of developing
severe disease and hospitalization is not only reassuring concerning the
safety of ACEi/ARB in patients with COVID-19 but also point towards the
urgent need for an adequately powered RCT to confirm these benefits.
Till such time, our meta-analysis adds to current knowledge confirming
not only the safety of ACEi/ARB in patents with COVID-19 but also
possible benefit in terms of reduction in death.
These findings are in keeping with the results of a meta-analysis of
three studies with 70346 patients with non-COVID pneumonia, where use of
ARB was associated with a significant reduction in the risk of
pneumonia-related morbidity (OR=0·55, 95% CI; 0·43-0·70,
p<0·01) and mortality (OR=0·55, 95% CI; 0·44-0·69,
p<0·01) (18). In another retrospective study on 313 elderly
patients, it was noted that the relative risk of developing a new
pneumonia of mixed aetiology was higher in patients who were not on an
ACEi when compared to those who were receiving ACE inhibitors [18%
vs. 7%; RR 2·65 (95% CI 1·31–5·35, p=0·007)] (28). lt would appear
that ACEi/ARB have a protective effect on pneumonia related pulmonary
injury, which may be of benefit in patients with COVID-19 since the
SARS-CoV-2 has a predilection for the lower respiratory tract.
Our meta-analysis has a few limitations. The six studies included for
analysis used different primary and secondary end-points that led to a
moderate degree of heterogeneity in the reported results; we
circumvented this by restricting our meta-analysis to clinically
relevant end-points of death, hospitalisation and severity of disease,
which resulted in negligible heterogeneity in our analysis on
hospitalisation and death. The number of patients in the individual
studies were small and there were various confounders, which were partly
addressed by pooling of the data from the individual studies. Last, but
not the least, due to a very small number of patients in the studies
that reported outcomes independently in patients with COVID-19 on an
ACEi or ARB, we were unable to assess the independent effect of ACEi or
ARB on death and severity of disease in patients with COVID-19.
The strength of our meta-analysis lies in the fact that in an evolving
infectious disease pandemic with acute consequences, where generation of
evidence at the earliest is crucial to guide management, the best way to
increase the predictability of the question in focus is to perform
pooled analysis, till results of a randomized controlled trial (RCT)
becomes available. By pooling data from multiple small observational
studies with multiple inherent confounding factors, and by performing a
meta-analysis, we have largely circumvented the problems associated with
the individual studies. This meta-analysis, highlighting the safety and
possibly beneficial effects of ACEi/ARB, shall help physicians use
ACEi/ARB in patients with COVID-19 till further information becomes
available. Secondly, since, the parameters assessed and the outcomes
analysed varied enormously between the six studies, we analysed
clinically relevant end-points including death, risk of hospitalisation,
and severity of illness.