Introduction
Several risk factors linked to poor COVID-19 outcomes have been identified early on, including cardiovascular diseases such as hypertension (1). Consequently, the possible impact of renin-angiotensin-aldosterone system (RAAS) inhibitors on COVID-19 related outcomes has emerged as a topic of interest (2) and their mechanisms of action– in particular, the potential upregulation of angiotensin-converting enzyme 2 (ACE2) which is associated with viral entry into bronchial cells (3). This has resulted in the rapid dissemination of numerous studies, mostly retrospective observational in nature, focusing on the risk of COVID-19 infection, disease severity, and/or disease outcomes in patients being treated with either angiotensin-converting-enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) since early 2020 (4-6).
As was the case in most early COVID-19 related research, the evidence comprised observational studies with notably small sample sizes and short durations of follow-up. Resultantly, a number of systematic reviews were swiftly published in attempt to offer a more substantial view by aggregating findings of these small-scale studies. These meta-analyses have offered tentative insights into all three areas of interest with regards to the use of RAAS inhibitors in times of COVID-19: (i) risk of infection, usually measured as the share of positive PCR tests within a study cohort; (ii) risk of severe COVID-19, with various underlying definitions ranging from hospitalisation due to the disease to the requirement for mechanical ventilation; and (iii) the risk of mortality. While there were similarities between some of the published results – e.g. indicating, in general, no association between RAAS inhibitor use and risk of COVID-19 infection – other results were more varied and the findings are still controversial/conflicting (4-6). A logical next step, besides conducting additional systematic reviews/meta-analyses, is to perform a systematic review of systematic reviews (also known as umbrella review), thereby taking advantage of the availability of high-level evidence and providing an opportunity to contrast and compare (7). The aim of this umbrella review and meta-analysis, therefore, was to assess the effect of ACEIs/ARBs on COVID-19 related outcomes by summarising the currently available, aggregate evidence.