Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Mortality Among COVID-19 Patients: A Systematic Review and Meta-Analysis

  1. Tarek Kashour
  2. Aref A. Bin Abdulhak
  3. Haytham Tlayjeh
  4. Leslie C. Hassett
  5. Anas Noman
  6. Ala Mohsen
  7. Mouaz H. Al-Mallah
  8. Imad M. Tleyjeh

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Abstract

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are known to increase the expression of angiotensin converting enzyme 2 receptor, which has been shown to be the receptor for the acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2).

Areas of Uncertainty:

Based on these observations, speculations raised the concerns that ACEIs/ARBs users would be more susceptible to SARS-CoV-2 infection and would be at higher risk for severe COVID-19 disease and death. Therefore, we systematically reviewed the literature and performed a meta-analysis of the association between prior use of ACEIs and ARBs and mortality due to COVID-19 disease.

Data Sources:

A comprehensive search of several databases from November 2019 to June 18, 2020 was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process and Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus. Medrxiv.org was also searched for unpublished data.

Therapeutic Advances:

Nine studies with a total of 18,833 patients infected with SARS-CoV-2 met our eligibility criteria. Prior use of ACEIs and/or ARBs was associated with reduced mortality among SARS-CoV-2-infected patients, with a pooled adjusted relative risk (aRR) from 6 studies of 0.63, 95% confidence interval (CI) (0.42–0.94) (I 2 = 65%). Three studies reported separately on ACEIs or ARBs and their association with survival among SARS-CoV-2-infected patients, with a pooled adjusted relative risk of 0.78, 95% CI (0.58–1.04) (I 2 = 0%) and 0.97, 95% CI (0.73–1.30) (I 2 = 0%) respectively. The results of sensitivity analyses were consistent with the main analysis.

Conclusion:

Our meta-analysis suggests that use of ACEIs/ARBs is associated with a decreased risk of death among SARS-CoV-2-infected patients. This finding provides a reassurance to the public not to stop prescribed ACEIs/ARBs because of fear of severe COVID-19.

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  1. Version published to 10.1097/mjt.0000000000001281
  2. ScreenIT

    SciScore for 10.1101/2020.05.06.20093260: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Experimental Models: Organisms/Strains
    SentencesResources
    Two authors independently (AB and IT) examined eligible studies.
    AB
    suggested: RRID:BDSC_203)
    Software and Algorithms
    SentencesResources
    Search Strategy: Medline was searched from November 2019 through May 3, 2020, without language restriction for eligible studies.
    Medline
    suggested: (MEDLINE, RRID:SCR_002185)
    ClinicalTrial.org and medrxiv.org were also searched using similar PubMed search terms.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    The statistical software Review Manager, version 5.3.5 (The Nordic Cochrane Center, The Cochrane Collaboration, 2018, Copenhagen, Denmark) was used for all analyses.
    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:
    Our inferences from this meta-analysis are, however, weakened by limitations inherent to the meta-analysis and the individual studies. Given the observational design of included studies and retrospective data collection, the possibility that the observed association between ACEI/ARB use and COVID-19 outcome was affected by bias or confounding should be considered. For example, comorbidities and severity of illness are known confounders that are associated with ACEI/ARB intake and mortality and the healthy user effect could theoretically explain a potential role for ACEI/ARB in infection outcome. However, the opposite could also be the case where the sicker patients have more exposure to ACEI/ARB because patients with hypertension and cardiovascular risk factors have higher mortality from COVID. Moreover, the combined effect estimate from the studies that used regression models to adjust for possible confounders including age, comorbidities, and severity of illness—although the models were not uniform— supports our conclusions. As with any observational study, residual confounding cannot be fully excluded. Given our findings, it becomes ethically concerning to continue to enroll patients in the ongoing randomized trials that are testing the hypothesis that stopping/replacing chronic treatment with ACEI or ARB improves outcomes in symptomatic SARS-CoV2-infected patients. We are aware of at least 5 trials listed on clinicaltrias.gov. (Table 3). Although our study suggests that t...

    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 10.1101/2020.05.06.20093260 on medRxiv