Quality assessment
Overall confidence in the results was ‘moderate’ for 10 (21.3%) reviews
(18, 24, 25, 29, 36, 40-42, 55, 58), ‘low’ for 15 (30.6%) reviews (4,
5, 19-21, 26, 27, 30, 33, 44, 48-50, 54, 59), and ‘critically low’ for
22 (44.9%) reviews (6, 16, 17, 22, 23, 28, 31, 32, 34, 35, 37-39, 43,
45-47, 51-53, 56, 57) (Supplementary file 5 ). Considering the
critical domains, most reviews were considered to have had a
satisfactory technique for the statistical combination of results (n=45,
95.7%) (4-6, 16-21, 23-56, 58, 59) and for assessing risk of bias
(n=38, 80.1%) (4-6, 16, 18-22, 24-27, 29, 30, 33-37, 39-45, 47-52,
54-56, 58, 59). Less reviews were favourably considered in terms of
accounting for risk of bias when interpreting and discussing the results
(n=32, 68.1%), with appropriate conduct of publication bias (n=33)
(4-6, 16, 18-20, 22-26, 29-32, 36, 37, 40-44, 46, 48-50, 52, 55, 56, 58,
59), and only 15 (31.9%) reviews referred to the review methods being
established a priori (18, 21, 24, 25, 27, 29, 33, 36, 40-42, 51, 54, 55,
58).
Effect of ACEIs/AEBs (as a
one group) on the study outcomes
Overall, the effect of ACEIs/ARBs on nine COVID-19 related clinical
outcomes were evaluated (Table 1). The combined pooled meta-analysis
estimates indicated that ACEIs/ARBs used was associated with a
significant reduction in three clinical outcomes including death
(OR=0.80, 95%CI=0.75-0.86; I2 = 51.9%)
(Figure 2 ) death/ICU admission as composite outcome (OR=0.86,
95%CI= 0.80-0.92; I2= 43.9%) (Figure 3 ) and severe COVID-19
infection (OR=0.86, 95% CI=0.78-0.95; I2 = 68%) (Figure 4 );
on the other hand, ACEIs/ARBs was associated with a significant increase
in hospitalisation (OR=1.23, 95%CI=1.04-1.46; I2= 76.4%)
(Figure 5 ). However, there was insignificant association with
each of ICU admission (Figure 6 ), risk of acquiring COVID-19
infection (Figure 7 ), use of mechanical ventilator
(Figure 8 ), risk of SARS (Figure 9 ), and risk of
severe pneumonia (Figure 10 ).
However, the sub-group analyses indicated different results for some of
the outcomes (Table 2). Firstly, despite the consistent significant
reduction in death in association with ACEIs/ARBs use regardless of
studies’ crude/adjusted measure of effects, peer-review status and
hypertension use status, there was a trend toward lower protective
effective of ACEIs/ARBs on death as the quality of the studies enhanced
from critically low (OR=0.75, 95%CI=0.66-0.85; I2=
60.4%) to moderate (OR=0.85, 95%CI=0.75-0.96; I2=
53.4%) (Supplementary file 6A ;Table 2). Similarly, the
significant reduction in death/ICU admission associated with ACEIs/ARBs
appeared to be higher among the studies which presented adjusted measure
of effects (adjusted: OR=0.63, 95%CI=0.47-0.84 vs. crude: OR=0.87,
95%CI=0.81-0.93); and the pooled estimates for association ranged from
insignificant association among the critically low-quality studies
(OR=0.94, 95%CI=0.84-1.06; I2 = 57.4%) to a
significantly higher reduction among the moderate quality studies
(OR=0.74, 95%CI=0.63-0.85; I2 = 18.9%);
(Supplementary file 7A ;Table 2; besides, the significant
protective impact of ACEIs/ARBs on death/ICU admission was observed only
among peer-reviewed studies (peer-reviewed: OR=0.85, 95%CI=0.79-0.92
vs. non-peer reviewed: OR=0.89, 95%CI=0.75-1.10) and studies included
hypertension patients (OR=0.85, 95%CI=0.80-0.90) Supplementary
file 7A ;Table 2).
Likewise, the protective effect of ACEIs/ARBs use on severe COVID-19
infection was observed only among: peer-reviewed studies (peer-reviewed:
OR=0.89, 95%CI=0.83-0.96 vs. non-peer reviewed: OR=0.82,
95%CI=0.66-1.01), studies that did not recorded the hypertension status
of their patients (OR=0.85, 95%CI=0.76-0.96) and critically low-quality
studies (OR=0.69, 95%CI=0.53-0.92) and in fact the protective effect
disappeared completely as the quality of the studies improved since
insignificant association was observed among both low and moderate
quality studies (OR=0.93, 95%CI=0.85-1.03; OR=0.89, 95%CI=0.77-1.04,
respectively) (Supplementary file 8A ;Table 2) . In
terms of ACEIs/ARBs’ increasing impact on hospitalisation, this impact
was demonstrated only among the studies which: presented adjusted
measure of effects (adjusted: OR=1.33, 95%CI=1.21-1.47 vs. crude:
OR=1.21, 95%CI=0.91-1.61), were not peer-reviewed (OR=1.45,
95%CI=1.10-10.20 vs. peer-reviewed: OR=1.11, 95%CI=0.90-1.31) and did
not record the hypertension status of their patients (OR=1.35,
95%CI=1.15-1.58) (Supplementary file 9A ;Table 2).