Association of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with risk of COVID‐19, inflammation level, severity, and death in patients with COVID‐19: A rapid systematic review and meta‐analysis

  1. Xiao Liu
  2. Chuyan Long
  3. Qinmei Xiong
  4. Chen Chen
  5. Jianyong Ma
  6. Yuhao Su
  7. Kui Hong

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

An association among the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin‐receptor blockers (ARBs) with the clinical outcomes of coronavirus disease 2019 (COVID‐19) is unclear. PubMed, EMBASE, MedRxiv, and BioRxiv were searched for relevant studies that assessed the association between application of ACEI/ARB and risk of COVID‐19, inflammation level, severity COVID‐19 infection, and death in patients with COVID‐19. Ten studies were included with 13,944 patients. ACEI/ARB therapy might be associated with the reduced inflammatory factor (interleukin‐6) and elevated immune cells counts (CD3, CD8). Meta‐analysis showed no significant increase in the risk of COVID‐19 infection (odds ratio [OR]: 0.95, 95% CI: 0.89‐1.05) in patients receiving ACEI/ARB therapy, and ACEI/ARB therapy was associated with a decreased risk of severe COVID‐19 (OR: 0.75, 95% CI: 0.59‐0.96, p  = 0.02) and mortality (OR: 0.57, 95% CI: 0.37‐0.87, p  = 0.009). Subgroup analyses showed among the general population, ACEI/ARB therapy was not associated with reduced risks of severe COVID‐19 infection (OR: 0.85, 95% CI: 0.66‐1.08, p  = 0.19) and all‐cause mortality (OR: 0.31, 95% CI: 0.13‐0.75), and COVID‐19 infection (OR: 0.97, 95% CI: 0.89‐1.05, p  = 0.45) were not increased. Among patients with hypertension, the use of an ACEI/ARB was associated with a non‐significant lower severity of COVID‐19 (OR: 0.73, 95% CI: 0.51‐1.03, p  = 0.07) and significant lower mortality (OR: 0.57, 95% CI: 0.37‐0.87, p  = 0.009), without evidence of an increased risk of COVID‐19 infection (OR: 1.00, 95% CI: 0.90‐1.12, p  = 1.00). On the basis of the available evidence, ACEI/ARB therapy should be continued in patients who are at risk for, or have COVID‐19, either in general population or hypertension patients. Our results need to be interpreted with caution considering the potential for residual confounders, and more well‐designed studies that control the clinical confounders are necessary to confirm our findings.

Article activity feed

  1. Version published to 10.1002/clc.23421
  2. ScreenIT

    SciScore for 10.1101/2020.05.20.20108399: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationStudy Selection: Studies were considered eligible for inclusion if they 1) were designed as a randomized controlled trial, case-control study, or cohort study and 2) assessed the relationship between ACEI/ARB use and the level of inflammation, disease severity, and mortality in patients with COVID-19.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Literature Search: Two authors (L X. and Y.L) independently searched the PubMed and Embase databases for published articles and the preprint platforms medRxiv (https://www.medrxiv.org/) and bioRxiv (https://www.biorxiv.org/) (since many studies are available on these websites prior to publication, which allows for collection of the latest data) without language restrictions.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    bioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    Statistical Analyses: RevMan5.3 (Review Manager [RevMan]
    RevMan
    suggested: (RevMan, RRID:SCR_003581)
    ], version 5.3, Cochrane Collaboration) software was used for statistical data processing, and the OR and 95% CIs were used to estimate the effect.
    Cochrane Collaboration
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Study Limitations: Our research has several limitations. First, all of the included articles were observational and therefore cannot confirm the cause-and-effect relationship between ACEI/ARB therapy and the clinical prognosis of patients with COVID-19; a large-scale RCT is needed to confirm our results. Second, coexisting conditions such as hypertension have been shown a key prognostic determinant (e.g. severity and mortality) in patients with COVID-19. The guidelines recommend that patients with hypertension and COVID-19 continue their ACEI/ARB therapy, and our study reinforced this recommendation and further showed that the use of ACEI/ARB therapy might be associated with better clinical outcomes in the general population with COVID-19 and in hypertensive patients with COVID-19. However, the benefit of RAAS inhibitors in non-hypertensive patients might differ from those with hypertensive patients. Due to data limitations, we cannot analyze the severity and clinical prognosis of ACEI/ARB therapy in patients with COVID-19 without hypertension. Third, studies have shown that ACEIs and ARBs may play different roles in patients with COVID-19, due to limited data, we were unable to perform subgroup analyses of ACEIs and ARBs. Fourth, some characteristic clinical values (e.g., drug variables) were missing. For example, the specific details of RAAS inhibitors were lacking in all studies, which might have impact on our results. Fifth, considering that all of the included studies we...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.05.20.20108399v2 on medRxiv
  4. Version published to 10.1101/2020.05.20.20108399v1 on medRxiv