Discussion
This umbrella review for the first time combined all the available evidence so far from observational studies on the impact of ACEIs/ARBs on COVID-19 clinical outcomes (47 systematic review studies which reported 213 meta-analyses) into one pooled estimate. The collective, combined pooled estimates indicated evidence of statistically significant reduction in mortality, death/ICU admission and severe COVID-19 infection in association with ACEIs/ARBs use, but significant increase in the risk of hospitalisation (Table 1). Interestingly, there was no evidence of any significant association between ACEIs, or ARBs and any of the nine COVID-19 related clinical outcomes analysed in our study.
Although the magnitude of observed impact of ACEIs/ARBs use on reducing mortality was decreasing as the quality of studies improved (Table 2), the evidence were overall mostly consistent across all the sub-group analyses including a greater impact among studies that included hypertensive patients compared with studies that did not record the hypertension status of their study population (Table 2). In terms of death/ICU admission, the quality of the evidence was even better because the impact of ACEIs/ARBs use was greater and significant only among: moderate-quality studies, peer-reviewed studies and studies with hypertensive patients; however, the impact was significant regardless of whether the measure of effects was crude or adjusted, even though the impact was greater among studies with adjusted measure of effects compared those studies with crude measure of effects (Table 2). In contrast, the quality of the evidence for the impact of ACEIs/ARBs use on severe COVID-19 was low since the significant reduction was only observed among critically-low quality studies and in fact, the significant association disappeared as the quality of the studied enhanced from critically low quality to either low or moderate quality (Table 2).
In terms of the impact of ACEIs/ARBs on hospitalisation, the quality of the evidence was low because the significant association was not apparent when the data were analysed by the quality of the studies, even though the magnitude of the effect was almost consistent across the various quality of the studies; besides, the significant increase in hospitalisation was observed only among: studies that reported adjusted measure of effects, non-peer reviewed studies and studies that did not recorded the hypertensive status of their study population (Table 2).
The sub-group analyses demonstrated low-quality evidence regarding the different impact of ACEIs and ARBs (as separate groups) (Table 2). This observed difference has been suggested to be due to the increased level of angiotensin-II, which occurs following ARBs treatment but not ACEIs, which in turn imposes an increased substrate load on ACE2 enzyme requiring its upregulation (61); hence facilitates COVID-19 virus cell entry and its subsequent infectivity/pathogenicity (62). Furthermore, the increase in ACE2 activity demonstrated in patients with hypertension, either due to the pathophysiology of hypertension itself (63) or administration of ACEIs/ARBs as antihypertensive medications (64), could at least partially explain some of our study findings as why ACEIs/ARBs had significant greater impact on certain COVID-19 clinical outcomes (i.e., mortality, death/ICU admission) only among studies that included patient with hypertension.
Several hypotheses (related to the pathophysiology of COVID-19 infection and functions of ACE2) can explain the observed impact of ACEIs/ARBs in our current studies. The adverse negative effects of ACEIs/ARBs could be due to ACEIs/ARBs ability to cause upregulation of ACE2 expression (the cell entry point for COVID-19); hence facilitate and enhance COVID-19 viral binding and cell entry (64); whereas the positive protective effects could be through ACEIs/ARBs blockage of the harmful angiotensin II- AT1R axis and their effects on angiotensin II expression leading to subsequent increase in the level of the protective angiotensin 1-7 and 1-9 which have anti-inflammatory and vasodilatory effects; hence potentially attenuating the cardiac and pulmonary damages (2). Genetic ACE2 polymorphism among some individuals has been also suggested as potential factor explaining, at least partially, the harmful effects on ACEIs/ARBs on COVID-19 outcomes (65).
It is worth to highlight that our study findings are still important despite the recently published randomised clinical trial (RCT) (66) which found insignificant differences in the mean number of days alive/out of the hospital between those assigned to discontinue vs continue ACEIs or ARBs. This is because of certain points that are related to the findings from this RCT. First, this RCT was designed to evaluate the impact of continuing ACEIs or ARBs vs. their discontinuation after contracting COVID-19 rather than evaluating ACEIs/ARBs use vs. non-use of these medication which was the focus of most of the observational studies involved in our current study. Secondly, the RCT included only patients with mild or moderate COVID-19 with more than half of the participants (57%; n=376) having mild COVID-19, and evaluated only two COVID-19 related clinical outcomes, namely days alive (mortality) and out of hospital days; hence leaving a big gap in the evidence around ACEIs/ARBs’ impact on other important COVID-19 clinical outcomes as well as limiting generalisability to patients with severe COVID-19. Furthermore, although the RCT’s participants were all hypertensive patients, about one-third (~31%) and ~1% had diabetes and heart failure, respectively, which further limits the generalisability of the RCT’s findings to these conditions for which ACEIs/ARBs are commonly indicated. Moreover, the RCT’s participants were all from Brazil and hence extending the findings to other races or ethnicities will be limited; this is particularly importantly because there are evidence demonstrating that there are potential genetic variants of renin, angiotensinogen, ACE, angiotensin II and ACE2 among various populations that influence the function of the renin-angiotensin aldosterone system; hence affecting someone’ response to the COVID-19 infection (67).
Strengths and limitations
This review presents the most comprehensive systematic overview on the impact of RAAS inhibitors on COVID-19 related clinical outcomes, with a wide range of sensitivity (sub-group) analyses to assess the robustness of the evidence. None of the pooled meta-analysis estimates for the nine studied outcomes was affected/dominated by an individual study. Although most of the included studies were classified as ‘low’ or ‘critically low’ quality using AMSTAR 2 tool, it is widely acknowledged that the AMSTAR 2 tool has a high standard with most reviews rated as ‘critically low’ (68, 69). The AMSTAR 2 tool is also prone to subjective biases (70) , and assessment results are at the discretion of the reviewers regarding what is a “comprehensive” literature search or “satisfactory” explanation of heterogeneity or risk of bias assessment (70); therefore, quality assessment was conducted fully independent in this review. Alternatives tools to AMSTAR 2 exist such as the ROBIS tool, however the measurement categories are found to be broadly similar with the AMSTAR 2 tool considered more reliable (70).
Conclusion
Collective evidence so far from observational studies indicate a good quality evidence on the significant association between ACEIs/ARBs use and reduction in death and death/ICU admission (as a composite outcome). Additionally, ACEIs/ARBs use was found to be associated with a significant reduction in severe COVID-19 but a significant increase in hospitalisation; however, the evidence for these two outcomes was of poor quality; hence, cautious interpretation of these findings is required. Interestingly, findings for some of the clinical outcomes were dependent on whether the included patients had hypertension or not. Overall, our study findings further support the current recommendations of not discontinuing ACEIs/ARBs therapy in patients with COVID-19 due to the lack of good quality evidence on their harm but rather it could be beneficial to patients.