Renin–angiotensin system inhibition and risk of infection and mortality in COVID‐19: a systematic review and meta‐analysis

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, enters human cells by binding of its viral protein to the aminopeptidase angiotensin-converting enzyme 2 (ACE2). This has led to speculation whether treatment with renin-angiotensin system (RAS) inhibitors was associated with an increased likelihood of a positive test for COVID-19 and risk of mortality. Aims: We performed a systematic review and meta-analysis to investigate whether RAS inhibitors increased the likelihood of a positive test or death/severe illness in patients with COVID-19. Methods: A systematic search of MEDLINE, PubMed and EMBASE was conducted for studies stratified by the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Pooled analysis was performed using a random-effects model. Results: Seven trials of 73 122 patients were included. Overall, 16 624 (22.7%) patients had a positive COVID-19 test and 7892 (10.8%) were on a RAS inhibitor. RAS inhibitors were not associated with higher likelihood of a positive COVID-19 test result (odds ratio (OR) 0.97 (95% CI 0.97-1.05, P = 0.48) with low heterogeneity. This was comparable when stratifying by use of each medication class. The use of RAS inhibitors was also not associated with mortality or severe illness (OR 0.89, 95% CI 0.73-1.07, P = 0.21) with moderate heterogeneity. Conclusion: Use of ACEI or ARB was not associated with a heightened susceptibility for a positive diagnosis of COVID-19. Furthermore, they were not associated with increased illness severity or mortality due to COVID-19. Randomised controlled trials are needed to address definitively the potential benefits or harms of RAS inhibitors in patients with COVID-19.

Update Alert 7: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults

“…New evidence since the publication of our original review includes results from a randomized controlled trial and 4 large database studies that included patients with a mix of disease severity ( 16–19 , 23 ). These studies consistently found that ACEI or ARB use was not associated with a higher risk for SARS-CoV-2 infection, findings which are further supported by 5 systematic reviews or meta-analyses ( 11 , 14 , 92–94 ). Because we consider these findings to be stable (meaning that future studies are likely to have the same results), we will no longer do literature surveillance on this KQ and will retire it from our living review.…”

“…These studies are all relevant to key question (KQ) 2 about the association of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) use and coronavirus disease 2019 (COVID-19) severity, and they support our prior conclusion that ACEI or ARB use is not associated with a higher risk for severe COVID-19 illness. Two systematic reviews also address KQ1, adding support to our prior conclusion that ACEI or ARB use is not associated with an increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection ( 11 , 14 ).…”

Role of Ecologic ACE I/D Polymorphism Data Towards Prediction of COVID-19 Epidemiology

“…D allele of ACE I/D polymorphism mediates higher ACE expression) [10] and have been associated with acute respiratory distress syndrome (ARDS), hypertension, obesity/metabolic syndrome, cardiovascular risk, and abnormal blood clotting tendency; all of which represent clinical hallmarks of severe COVID-19 disease [reviewed in [4,11]]. In contrast, no clinical advantage was observed in COVID-19 patients treated with ACE inhibitors or angiotension receptor blockers (mediating high ACE2 and low angiotension II) [12], suggesting that further efforts are needed to fully comprehend the role of RAAS in COVID-19. Therefore, the present study employed an ecological meta-regression design to evaluate the ACE1 I/D genotypic data in relation to the observed differences in COVID- 19 inhabitants), GDP/capita (PPP), current health expenditure/capita (PPP), healthy life expectancy at birth, DALY diabetes mellitus, DALY hypertensive heart disease and DALY respiratory infections as retrieved from the World Health Organization website www.who.int/countries/en/.…”

Losartan promotes cell survival following SARS-CoV-2 infection in vitro

“…Stopping the use of ARBs was recommended in the early phase of the pandemic due to the concern over possible increase in viral load [28, 29]. Recent studies have revealed safety of ARBs in patients with COVID-19 [30, 31]. Importantly, a recent study proposed that Losartan, an ARB, could ameliorate complications, especially of acute respiratory distress syndrome (ARDS) associated with COVID-19 [27].…”