Renin–angiotensin–aldosterone system blockers and region-specific variations in COVID-19 outcomes: findings from a systematic review and meta-analysis

  1. Upinder Kaur
  2. Sankha Shubhra Chakrabarti
  3. Tejas K. Patel

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Abstract

Coronavirus disease 2019 (COVID-19) has been observed to cause a high mortality in people with cardiometabolic diseases. Renin–angiotensin–aldosterone system (RAAS) blockers enhance the expression of ACE2, the binding receptor of SARS-CoV-2, and can enhance viral infectivity. We aim to provide a pooled estimate of the effect of RAAS blockers on COVID-19 outcomes.

Methods:

A literature search was performed using MEDLINE/PubMed, Google Scholar and preprint servers. All clinical studies analyzing the effect of RAAS blockers on clinical outcomes in COVID-19 patients were included in this study. Newcastle–Ottawa scale was used for quality assessment of studies. MOOSE checklist was followed. Mortality and severity outcomes were recorded as pooled odds ratio (OR) with 95% Confidence Intervals (CIs) and level of heterogeneity ( I 2 ). Odds of mortality was the primary outcome. Odds of severity, hospitalization, intensive care unit (ICU) admission, mechanical ventilation (MV), steroid use and acute kidney injury were the secondary outcomes. Severity outcomes were chosen depending upon the definition used by respective authors. Country-specific variations and effects of individual class of RAAS blockers were also explored.

Results:

In total 47 published studies were included in the final analysis, with a total of 26,432 patients from 31 studies in mortality analysis and 20,127 patients from 23 studies in severity analysis. No increased risk of mortality [Pooled OR 0.91 (0.65–1.26), I 2  = 89%] or severity [Pooled OR 1.08 (0.79–1.46), I 2  = 88%] was seen with RAAS blockers. The drug class was protective in hypertension [pooled OR 0.63 (0.46–0.86), I 2  = 58%]. Severity of COVID-19 outcomes was high for Europeans [Pooled OR 2.08 (1.52–2.85), I 2  = 77%] and US patients [Pooled OR 1.87 (1.62–2.17)]. Nearly 4 times higher risk of hospitalization and 2 times higher risk of ICU admission and MV were observed in US patients. Class-wise, angiotensin receptor blocker use was associated with 1.6 times higher odds of severity, mainly in Europeans.

Conclusion:

RAAS blockers are not associated with increased mortality in COVID-19 patients and should be continued in hypertensives. US and European patients are at higher risk of severe outcomes. Pharmacogenetic differences may explain the ethnicity-related variations.

Plain language summary

Effect of RAAS-blocking medicines on COVID-19 Background and aims: Higher deaths have been observed in COVID-19 patients who have other long-term diseases such as heart disease, diabetes, and high blood pressure. Many of these patients are prescribed a class of medicines called RAAS blockers (ramipril, telmisartan, etc). We studied whether the use of these medicines worsens the course of COVID-19 disease in these patients or causes excess deaths. Methods: We conducted a pooled analysis of 47 observational studies on the use of RAAS blocker drugs in COVID-19 patients. Results: We found that RAAS blockers do not cause excess deaths in patients with COVID-19. On the contrary, they have benefits if prescribed to those with high blood pressure. We also found that whereas European and US patients of COVID-19 taking these medicines had higher disease severity, this was not the case for Chinese patients. Conclusion: Theremay be some genetic and other factors responsible for differences by ethnicity.

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  1. ScreenIT

    SciScore for 10.1101/2020.09.09.20191445: (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

    Software and Algorithms
    SentencesResources
    Search Criteria: A comprehensive search was conducted in PubMed, Google Scholar and the preprint servers medrRxiv.org and bioRxiv.org using keywords: ACEI OR ACE-I OR Angiotensin converting enzyme inhibitors AND COVID-19/SARS-CoV-2, Angiotensin receptor blocker OR AT-1 receptor blocker OR Ang II blocker OR ARB AND COVID-19/SARS-CoV-2, RAAS blocker AND COVID-19/SARS-CoV-2, Aldosterone antagonist AND COVID-19/SARS-CoV-2, Renin inhibitor AND COVID-19/SARS-CoV-2.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Google Scholar
    suggested: (Google Scholar, RRID:SCR_008878)
    bioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    Data Extraction: From the included studies, data was extracted in a Microsoft Excel Sheet.
    Microsoft Excel
    suggested: (Microsoft Excel, RRID:SCR_016137)
    The meta-analysis was performed using Review Manager Software version 5.4.
    Review Manager
    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:
    This systematic review has some limitations. The pooled analysis is mainly based on observational studies, which are more likely to have study populations with difference in baseline characteristics and co-interventions than randomized controlled trials. The country specific subgroup analysis was based on only a small number of studies. Further, the current meta-analysis aimed to generate data related to RAAS blockers and therefore excluded those studies (n=11) which focussed on ACEI and ARB class in isolation and did not provide information about the outcomes in combined RAAS blocker class. We did not compare the outcomes between users of ACEIs and ARBs also. However, such analyses can be done in the future to deduce any class specific differences that can potentially influence COVID-19 outcomes.

    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.

  2. Version published to 10.1177/20420986211011345
  3. Version published to 10.1101/2020.09.09.20191445v1 on medRxiv
  4. Version published to 10.1101/2020.09.09.20191445v2 on medRxiv