key: cord-0801583-gea5229c
authors: Kurdi, Amanj; Abutheraa, Nouf; Akil, Lina; Godman, Brian
title: A systematic review and meta‐analysis of the use of renin‐angiotensin system drugs and COVID‐19 clinical outcomes: What is the evidence so far?
date: 2020-10-20
journal: Pharmacol Res Perspect
DOI: 10.1002/prp2.666
sha: 70370da2c020946c68a997bbaf9a4c6ceb473aff
doc_id: 801583
cord_uid: gea5229c

Conflicting evidence exists about the effect of angiotensin‐converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) on COVID‐19 clinical outcomes. We aimed to provide a comprehensive/updated evaluation of the effect of ACEIs/ARBs on COVID‐19‐related clinical outcomes, including exploration of interclass differences between ACEIs and ARBs, using a systematic review/meta‐analysis approach conducted in Medline (OVID), Embase, Scopus, Cochrane library, and medRxiv from inception to 22 May 2020. English studies that evaluated the effect of ACEIs/ARBs among patients with COVID‐19 were included. Studies’ quality was appraised using the Newcastle‐Ottawa Scale. Data were analyzed using the random‐effects modeling stratified by exposure (ACEIs/ARBs, ACEIs, and ARBs). Heterogeneiity was assessed using I(2) statistic. Several subgroup analyses were conducted to explore the impact of potential confounders. Overall, 27 studies were eligible. The pooled analyses showed nonsignificant associations between ACEIs/ARBs and death (OR:0.97, 95%CI:0.75,1.27), ICU admission (OR:1.09;95%CI:0.65,1.81), death/ICU admission (OR:0.67; 95%CI:0.52,0.86), risk of COVID‐19 infection (OR:1.01; 95%CI:0.93,1.10), severe infection (OR:0.78; 95%CI:0.53,1.15), and hospitalization (OR:1.15; 95%CI:0.81,1.65). However, the subgroup analyses indicated significant association between ACEIs/ARBs and hospitalization among USA studies (OR:1.59; 95%CI:1.03,2.44), peer‐reviewed (OR:1.93, 95%CI:1.38,2.71), good quality and studies which reported adjusted measure of effect (OR:1.30, 95%CI:1.10,1.50). Significant differences were found between ACEIs and ARBs with the latter being significantly associated with lower risk of acquiring COVID‐19 infection (OR:0.24; 95%CI: 0.17,0.34). In conclusion, high‐quality evidence exists for the effect of ACEIs/ARBs on some COVID‐19 clinical outcomes. For the first time, we provided evidence, albeit of low quality, on interclass differences between ACEIs and ARBs for some of the reported clinical outcomes.

conflicting findings which is a concern given the controversies with hydroxychloroquine and lopinavir/ritonavir. For instance, some studies [17] [18] [19] [20] [21] [22] have reported a lower risk of severe COVID-19 outcomes with ACEIs/ ARBs while another study 23 found a higher risk. Similarly, ACEIs/ARBs have been associated with lower mortality rates in some studies 17, 20, [24] [25] [26] [27] while others 23,28 reported higher mortality rates. We are also aware that two recently published systematic reviews 29, 30 containing 16 studies reported no evidence of any association between ACEIs/ARBs and mortality, severe COVID-19 outcomes, or acquiring COVID-19 infection; however, these studies only analyzed a limited range of outcomes, and did not report the effects of ACEIs and ARBs individually. The authors also did not undertake any subgroup analysis to explore the effect of potential confounders such as the study's quality and there are concerns that the findings may now be out-dated. Furthermore, one of these studies 30 only used narrative synthesis of the data. Consequently, we sought to undertake an updated and comprehensive evaluation of effect of ACEIs/ARBs use on all reported COVID-19-related outcomes, including exploration of any class differences, through a systematic review of the literature coupled with a meta-analysis. *This study reported data from two cohorts; hence it is included twice in the analyses.

TA B L E 2 Quality assessment score of the studies included into the systematic review and meta-analysis based on the using the Newcastle-Ottawa Scale and abstract screening for relevance, followed by selecting records for full-text screening and data extraction. At each stage, discrepancies were resolved through discussion until consensus was achieved. A third author (AK) verified the eligibility of the included studies. Odds ratio was resolved by involving a third researcher (AK) for discussion until a consensus was reached. Furthermore, interrater reliability measures such as kappa statistic and percentage agreement were also calculated. Some of the coauthors have used this approach before. 34

For each study outcome that was reported by more than one study, the results from individual studies were combined statistically using the random-effects meta-analysis model, stratified by the level of exposure (ACEIs/ARBs, ACEIs, ARBs); whereas for outcomes which were reported by only one study, narrative synthesis was used. For studies which did not report the summary statistics and measure of effects, we firstly used the reported primary statistics (number of patients with/without the outcomes in both exposed/unexposed group) to calculate the corresponding measure of effects (Odds ratios-OR) and their 95% confidence interval (95%CI), 35 and subsequently used these measure of effects in the random-effects meta-analysis; the random-effects model was used as it is considered the most appropriate model by most researchers since it allows the results to be generalizable to other populations as well as addresses the likely heterogeneity between the included studies. 36 Several subgroup analyses were also undertaken to explore the effect of potential confounders on the robustness and sensitivity of combined pooled estimates and included subgroup analyses based on whether the reported measure of effects was crude or adjusted, whether the study was peerreviewed or not, the study's methodological quality as per the risk of bias assessment was performed as well as the continent where TA B L E 3 Meta-analyses pooled estimates with 95%CI of the effects of ACEIs/ARBs on COVID-19 related clinical outcomes 

None.

The Odds ratio two independent reviewers (NA and LA) in assessing the risk of bias (kappa statistic = 0.79; percentage of agreement = 89% (24/27)). Table 4 ). Odds ratio

The (Figure 6 ; Table 3 ), regardless of any subgroup analysis (File S6; Table 4 ).

In a pooled analysis of eight and three studies, there was no signification association between hospitalization, hospital discharge rate and (Figure 7 ; Figure 8 and Table 4 ). Contrastingly, a significantly higher rate of hospital discharge was observed with ACEIs/ARBs but only Table 4 ). Two studies reported data on the duration of hospital stay. 

Among pertinent studies, there was no significant association between these outcomes and the use of ACEIs/ARBs Odds ratio

Results from the funnel plot (File S10) and Egger's asymmetry test for the death outcome, which was the only outcome whereby >10 studies were included in the meta-analysis, indicated statistically insignificant evidence of publication bias (bias coefficient:0.85, 95%CI: −2.23, 3.93, P = .445).

The pooled analyses in this updated systematic review and meta-analy- Our study findings also showed no significant association between ACEIs/ARBs and mortality, severe COVID-19 infection, or positive tests for COVID-19, in agreement with two previously published systematic reviews. 29, 30 This was despite the inclusion of more recently published studies, 18, 27, 40, 41, 49, 50, 53 which implies consistency of evidence. This is encouraging given the controversies were of poor quality and none performed adjusted analyses to account for potential confounders. Confounding by indication is of particular concern with comorbidities such as CVD and diabetes associated with more severe COVID-19 morbidity and mortality. [4] [5] [6] Similarly, the observed significant associations between ACEIs/ 

We believe this study is the first to provide a systematic, comprehen- Odds ratio have been published since our review. However, we included nonpeer-reviewed articles published in medRxiv to help address this.

There appears to be no evidence of association between ACEIs/ARBs use and a wide range of COVID-19-related clinical outcomes. However, good quality evidence exists for ACEIs/ARBs and higher odds of hospitalization, lower odds of death/ICU admission (as composite endpoint); but only low-quality evidence for higher ICU admission, ventilator use, hospital discharge and lower duration of hospital stay exists.

Furthermore, there is evidence, albeit of poor quality, of differences between ACEIs and ARBs with the latter being associated with significantly higher ICU admission but lower COVID-19 infection risk and severity. Given the continuing controversial and paradoxical clinical studies' findings and hypotheses, we believe it is necessary to continue to evaluate the effects of ACEIs/ARBs on COVID-19 clinical outcomes especially as more randomized studies are reported.

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guide topha rmaco logy.org, F I G U R E 1 0 Forest plot depicting pooled estimates for the association between use of ventilator/Intensive Care Unit admission and the three levels of renin-angiotensin system drug exposure (ACEIs/ARBs, ACEIs, ARBs) Odds ratio the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY, 59 and are permanently archived in the Concise

Guide to PHARMACOLOGY 2019/20. 60

Not required.

Nothing to declare.

Study conception and design: all authors; data collection and management: NA, AL; data analysis and interpretation: AK, BG; manuscript writing and drafting: AK, NA; manuscript reviewing and revising as well as providing constructive criticism and final approval: all authors.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Amanj Kurdi https://orcid.org/0000-0001-5036-1988

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