Risks of ACE Inhibitor and ARB Usage in COVID‐19: Evaluating the Evidence

  1. Krishna Sriram
  2. Paul A. Insel

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Abstract

Concerns have been raised regarding the safety of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with coronavirus disease of 2019 (COVID‐19), based on the hypothesis that such medications may raise expression of ACE2, the receptor for severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a literature review of studies ( n  = 12) in experimental animals and human subjects ( n  = 12) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. The findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses of ACEIs or ARBs than are typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. Available evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID‐19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications.

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  1. ScreenIT

    SciScore for 10.1101/2020.03.25.20043927: (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

    No key resources detected.

    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:
    As a caveat, changes in ACE2 levels in serum or urine may not reflect changes in tissue. 5) Epidemiological studies are largely unavailable in matched groups of patients infected with SARS-CoV-2, who have or have not been taking ACEIs/ARBs. One preliminary study, 50 examined 28 patients with severe COVID-19 and 18 patients with mild disease, all of whom also had hypertension. ARB use was associated with a reduction in risk of severe COVID-19 disease, morbidity and mortality, a result that contradicts the hypothesis that ARB/ACEI use is harmful. However, only small numbers of patients have been assessed. Based on the data summarized above, we conclude that current evidence, especially from human studies (Table 3), does not support the idea that treatment with ACEIs or ARBS produces pathophysiologically relevant increases in ACE2 protein abundance. The hypothesis that the use of these drugs increases SARS-CoV-2 virus infectivity and/or severity of COVID-19 is therefore not supported by the available evidence. It would thus seem prudent for patients to continue receiving these medications, as recently recommended by multiple health associations2 and other publications 51.

    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

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  2. Version published to 10.1002/cpt.1863
  3. Version published to 10.1101/2020.03.25.20043927v2 on medRxiv
  4. Version published to 10.1101/2020.03.25.20043927v1 on medRxiv