Evidence on the safety of antihypertensive medications is of paramount importance as about one-third of the world’s population is estimated to have hypertension [22] and this comorbidity is associated with increased mortality in patients with COVID-19 [23]. Since RAAS inhibitors were reported to affect the clinical outcome of COVID-19, either for good or worse [6, 11, 24], we pooled recent studies to provide stronger evidence on the effects of these drugs. In addition, we also performed multiple sub-meta-analyses (comparing class of antihypertensives) to identify the effect of specific drug classes. We found that COVID-19 patients taking RAAS inhibitors had an overall decreased risk of poor outcomes compared to those receiving non-RAAS inhibitors. However, based on our multiple sub-meta-analysis findings (Table 2), these effects were likely related to the underlying comorbidities for which specific antihypertensive class of drugs were indicated, and not necessarily due to the drugs themselves.
It is possible that the overall decreased risk of COVID-19 severity or mortality with the use of RAAS inhibitors could be related to the blockage of a rapidly progressing systemic inflammation that is frequently seen in severe COVID-19 cases [25]. For example, COVID-19 patients taking ACE/ARBs had lower levels of inflammatory markers, such as interleukin 6 (IL-6) [9], C-reactive protein (CRP) and procalcitonin [10], than those not taking these drugs. In addition, these classes of drugs could also help prevent hypokalaemia, a complication that was reported to occur in COVID-19 patients [26]. Hence, RAAS inhibitors may decrease poor clinical outcomes by limiting the deleterious effects of angiotensin-II in multisystem inflammation, as well as by preventing the occurrence of hypokalaemia [25, 26]. Further, these drugs could also circumvent SARS-CoV-2 induced ACE2 downregulation in host cells, so that the preventive effects of ACE2 against severe disease are not lost [27].
However, the apparent decrease in COVID-19 poor outcomes with RAAS inhibitors could also be due to the mere comorbidity differences among patients who took different class of antihypertensive drugs. This is supported by our sub-meta-analyses findings that showed both ACEIs and ARBs were not different from CCBs in terms of COVID-19 outcomes (Table 2). Interestingly, however, ACEIs and ARBs showed a decrease in poor COVID-19 outcomes, when each were compared to BBs (Table 2). Therefore, the overall decrease in poor COVID-19 outcomes with RAAS inhibitors relative to non-RAAS inhibitors could be related to a more severe cardiovascular comorbidity in patients taking certain non-RAAS inhibitors like BBs.
In fact, a recent study showed that the use of either ACEIs or ARBs does not increase ACE2 expression in human tissues [28]. This is in sharp contrast to a previous experimental study (in rats) that reported an increase in ACE2 expression with these drugs [3]. Note that, increased ACE2 expression with the use of RAAS inhibitors was the key pathophysiologic process that was hypothesised to be associated with an increase in SARS-CoV-2 entry to human cells and hence diseases severity. On the other hand, increased ACE2 expression was also thought to be associated with a decrease in COVID-19 severity and mortality, since ACE2 enhances the degradation of harmful angiotensins into cardioprotective ones. Hence, combining all the above evidences, RAAS inhibitor antihypertensive medications might not have any effect at all on the severity or mortality of COVID-19.
To the best of our knowledge, this systematic review and meta-analysis is a comprehensive one including the most recent studies and clinical outcomes of COVID-19 among patients taking major classes of antihypertensive drugs. However, our study has some limitations, majority of which are implicit to the studies included. First, even though all of the included papers were of good quality, propensity matching to address common confounders was performed in only few of the studies. Second, the number of studies included in our sub-meta-analyses (versus the main meta-analysis) (Table 2) were relatively small and this might affect our conclusions. The other limitation is that our interpretation of sub-meta-analysis findings were based on our clinical judgement that assumed prescription of BBs could occur in patients with worse cardiovascular comorbidity[16]. For instance, patients taking certain antihypertensives like BBs may not necessarily have a worse cardiovascular condition. Similarly, even though ACEIs are good choice of antihypertensives in patients without any comorbidity, they are also preferred drugs in those who had myocardial infarction or systolic dysfunction. On the other hand, the strength of this meta-analysis is that we excluded studies that compared hypertensive patients who were taking RAAS inhibitors to those that were not taking any form of antihypertensive (e.g. on dietary management). This helped us to have comparable groups in terms of comorbidity and severity of hypertension.