Renin Angiotensin System Inhibition and Susceptibility and Outcomes from COVID-19: A Systematic Review and Meta-analysis of 69,200 COVID-19 Patients

  1. Yi Zhang
  2. Shikai Yu
  3. Yawei Xu
  4. Bryan Williams

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Abstract

Background

Early observational studies suggested that the use of the renin angiotensin system (RAS) inhibitors, specifically angiotensin converting enzyme inhibitors or angiotensin receptor blockers, may increase the risk of infection with SARS-CoV-2 and adversely affect the prognosis or survival of infected patients. To explore the impact of RAS inhibitor use on the risk of SARS-CoV-2 infection and the prognosis of SARS-CoV-2 infected patients, from all published studies.

Methods and Findings

A systematic review and meta-analysis of the use of RAS inhibitors in relation to infection with SARS-CoV-2 and/or the severity and mortality associated with COVID-19 was conducted. English language bibliographic databases PubMed, Web of Science, OVID Embase, Scopus, MedRxiv, BioRxiv, searched from Jan 1st, 2020 to July 20th, 2020. 58 observational studies (69,200 COVID-19 patients and 3,103,335 controls) were included. There was no difference in the susceptibility to SARS-CoV-2 infection between RAS inhibitor users and non-users (unadjusted OR 1.05, 95% CI 0.90 to 1.21), (adjusted OR 0.93, 95% CI 0.85 to 1.02), (adjusted HR 1.07, 95% CI 0.87 to 1.31). There was no significant difference in the severe Covid-19 case rate between RAS inhibitor users and non-users (unadjusted OR 1.05, 95% CI 0.81 to 1.36), (adjusted OR 0.76, 95% CI 0.52 to 1.12), or in mortality due to COVID-19 between RAS inhibitor users and non-users (unadjusted OR 1.12, 95% CI 0.88 to 1.44), (adjusted OR 0.97, 95% CI 0.77 to 1.23), (adjusted HR 0.62, 95% CI 0.34 to 1.14).

Conclusions

In the most comprehensive analysis of all available data to date, treatment with RAS inhibitors was not associated with increased risk of infection, severity of disease, or mortality due to COVID-19. The best available evidence suggests that these treatments should not be discontinued on the basis of concern about risk associated with COVID-19.

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  1. Version published to 10.1101/2020.10.03.20206375v2 on medRxiv
  2. ScreenIT

    SciScore for 10.1101/2020.10.03.20206375: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationWe planned to use the Cochrane Risk of Bias tool to evaluate the risk of bias in any randomized clinical trials (RCTs), but only one retrospective interim analysis of an unfinished RCT study was identified for this meta-analysis which was treated as a cohort study and evaluated with NOS.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableThe following information was extracted from each study: study identifier, study design, country, study size, mean/median age, male sex proportion, quantitative outcomes, effect estimators (Odds ratios [ORs] or Hazard ratios [HRs]) and adjusted covariates if available.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    6 Eligibility criteria, search strategy and study selection: We performed a systematic literature search for studies of any design and in any setting in electronic bibliographic databases including PubMed, Web of Science, OVID Embase, and Scopus from Jan 1st, 2020 to July 20th, 2020, using a comprehensive search strategy as described in eAppendix 1 in the Supplement.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    We also manually searched preprint platforms (MedRxiv and BioRxiv), coronavirus resource centers of N Engl J Med, JAMA, BMJ and the Lancet, and checked reference lists of eligible studies to find additional studies.
    BioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    We planned to use the Cochrane Risk of Bias tool to evaluate the risk of bias in any randomized clinical trials (RCTs), but only one retrospective interim analysis of an unfinished RCT study was identified for this meta-analysis which was treated as a cohort study and evaluated with NOS.
    Cochrane Risk of Bias
    suggested: None
    All statistical analyses were conducted using Reviewer Manager 5.3 (The Nordic Cochrane Center, The Cochrane Collaboration, 2018, Copenhagen, Denmark) and STATA version 12.0
    Cochrane Collaboration
    suggested: None
    STATA
    suggested: (Stata, RRID:SCR_012763)

    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:
    3 The present finding needs to be interpreted, mindful of the limitations of observational cohort studies. It is noteworthy that in most analyses, there is substantial risk of bias indicated by the high I2 value in both main and subgroup analyses. This was mainly attributable to the inherent weakness of observational studies and the inevitable possibility of confounding. The association of various outcomes or with prior pharmaceutical treatments are commonly influenced by numerous confounders, especially the indication for treatment, which often varies according to comorbidities. The fact that RAS inhibitor medications are recommended as a foundation treatment for hypertension or many of the comorbidities associated with increased risk of mortality from COVID-19, i.e. diabetes, cardiac disease and chronic kidney disease, and the fact that all of these conditions are more common with advancing age, highlights the obvious potential for confounding in the relationship between RAS inhibitor use and adverse outcomes from COVID-19. These confounding can only really be overcome by randomized allocations to treatments in controlled trials and such trials are ongoing.13

    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 10.1101/2020.10.03.20206375v1 on medRxiv