








key: cord-256422-4crdzojb
authors: Garg, Aakash; Rout, Amit; Sharma, Abhishek; Fiorello, Brittany; Kostis, John B.
title: Association of Renin Angiotensin System Blockers With Outcomes in Patients with COVID-19
date: 2020-09-14
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.09.010
sha: 
doc_id: 256422
cord_uid: 4crdzojb

nan

To the Editor: Conflicting findings have been reported regarding the safety of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) during the Covid-19 pandemic. 1, 2 In reference to the recently published review outlining the relationship between renin angiotensin system (RAS) and Covid-19 infection, 3 we present additional data regarding the association of RAS inhibitors with outcomes in patients with Covid-19.

Covid-19 pandemic affecting more than 4.5 million people across the globe has caused significant morbidity and mortality. 4 Angiotensin converting enzyme 2 (ACE-2) has been implicated in the entry of SARS-Cov-2 virus into host cells. 5 Since renin angiotensin system (RAS) antagonists have been suggested to upregulate ACE2 in few animal models, concerns have been raised that these drugs might be associated with increased risk of infection or severe disease from Covid-19. 6, 7 Whether such patients on ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) should continue these drugs has become a matter of debate. Accordingly, we performed a meta-analysis to study the cumulative evidence for association of ACEI/ARB use with risk of mortality and severe illness with Covid-19.

A comprehensive search in electronic databases (MEDLINE and EMBASE) was performed for studies published between November 01, 2019 and May 31, 2020. The following key words were used for search in different combinations: "Coronavirus 2019", "Covid-19", "SARS-Cov-2", "Renin angiotensin system", "Angiotensin converting enzyme", "Angiotensin converting enzyme inhibitors", "ACEI", "Angiotensin receptor blockers"; "ARB", and "Outcomes". Inclusion criteria were studies published in peerreviewed journals and reporting outcomes based on ACEI/ARB use in Covid-19. Two J o u r n a l P r e -p r o o f reviewers (A.G. and A.R.) screened the study titles and abstracts followed by full manuscript evaluation. From individual studies, we collected baseline characteristics of patients including proportion of patients with HTN and those taking ACEI/ARB. The primary outcome was in-hospital mortality. Secondary outcome was severe/critical illness [need for intensive care unit, invasive mechanical ventilation, or mortality] as defined per individual study protocol. We used the Cochrane review manager 5.3 for statistical analysis. Random-effects model with Mantel-Haenszel method was used to calculate the pooled odds ratios (OR) with 95% confidence intervals (CI) for each end-point. This meta-analysis was conducted in accordance with the PRISMA guidelines. 8 After initial screening and full text review, 15 studies were identified to report outcomes based on ACEI/ARB use in patients with confirmed Covid-19. 1, 2, 5, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] One study was excluded due to retraction by the authors. 10 accounting for worse outcomes in these patients. 21 While the role of ACE2 as cellular receptor for SARS-CoV-2 entry into host cells is proven, human studies have been inconclusive with respect to the effect of RAS inhibitors on ACE2 levels. 22 Furthermore, contradictory to the speculation that RAS inhibitors-mediated ACE-2 upregulation might increase risk of infection, ACE2 expression has been actually suggested to protect against severe lung injury in these patients. 23 There are several limitations to our study. First, our pooled analyses were based on observational studies that have inherent risk of bias due to confounding variables.

Patients taking ACEI/ARBs have increased burden of other comorbidities that might make them more prone to fatality. However, despite this potential bias, we observed no association of ACEI/ARB use with increased risk of mortality or severe illness. Second, ascertainment of drug data is limited in individual retrospective studies. It remains unknown whether continuation or withdrawal of these drugs during hospitalization influenced outcomes in patients admitted with Covid-19.

In conclusion, our study provides reassurance that there is no increased risk of mortality or severe illness in patients using ACEI/ARB compared to non-users. In patients with hypertension, ACE/ARB use might be associated with reduced mortality, however these findings need to be confirmed in prospective randomized controlled trials. 

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