An umbrella review and meta-analysis of renin-angiotensin system drugs use and COVID-19 outcomes

Background: Despite the availability of extensive literature on the effect of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) on COVID-19 outcomes, the evidence is still controversial. We aimed to provide a comprehensive assessment of the effect of ACEIs/ARBs on COVID-19-related outcomes by summarising the currently available evidence. Methods: An umbrella review was conducted using Medline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 1 February 2021. Systematic reviews with meta-analysis that evaluated the effect of ACEIs/ARBs on COVID-19-related clinical outcomes were eligible. Studies' quality was appraised using the AMSTAR 2 Critical Appraisal Tool. Data were analysed using the random-effects modelling including several subgroup analyses. Heterogenicity was assessed using I ² statistic. The study protocol was registered in PROSPERO (CRD42021233398) and reported using PRISMA guidelines. Results: Overall, 47 reviews were eligible for inclusion. Out of the nine COVID-19 outcomes evaluated, there was significant associations between ACEIs/ARBs use and each of death (OR = 0.80, 95%CI = 0.75–0.86; I ² = 51.9%), death/ICU admission as composite outcome (OR = 0.86, 95%CI = 0.80–0.92; I ² = 43.9%), severe COVID-19 (OR = 0.86, 95%CI = 0.78–0.95; I ² = 68%) and hospitalisation (OR = 1.23, 95%CI = 1.04–1.46; I ² = 76.4%). The significant reduction in death/ICU admission, however, was higher among studies which presented adjusted measure of effects (OR = 0.63, 95%CI = 0.47–0.84) and were of moderate quality (OR = 0.74, 95%CI = 0.63–0.85). Conclusions: Collective evidence from observational studies indicate a good quality evidence on the significant association between ACEIs/ARBs use and reduction in death and death/ICU admission, but poor-quality evidence on both reducing severe COVID-19 and increasing hospitalisation. Our findings further support the current recommendations of not discontinuing ACEIs/ARBs therapy in patients with COVID-19.