Deleterious drugs in COVID-19: a rapid systematic review and meta-analysis

  1. Michael Holder
  2. Catherine Heeney
  3. Stephen Malden
  4. Uditha Perera
  5. Aziz Sheikh

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Abstract

Background

Concerns have been expressed about a number of drugs that potentially worsen outcomes in patients with COVID-19. We sought to identify all potentially deleterious drug groups in COVID-19 and critically assess the underpinning strength of evidence pertaining to the harmful effects of these drugs.

Methods and findings

We performed a rapid systematic review, searching Medline, Embase and two COVID-19 portfolios (WHO COVID-19 database and NIH iSearch COVID-19 portfolio) for papers and preprints related to primary studies investigating drugs identified as potentially deleterious. Primary outcomes were direct measures of susceptibility to infection, disease severity and mortality. Study quality was assessed using the National Heart, Lung, and Blood Institute quality assessment tools. Random-effects meta-analyses were used for data synthesis with further subgroup analyses where possible for specific outcome, study design, statistical adjustment and drug groups when two were combined. Sensitivity analyses were performed by removing any studies at high risk of bias and by publication status.

49 observational studies (15 peer-reviewed papers and 34 preprints) reported primary outcomes for eight drug groups hypothesised to be deleterious. Meta-analysis showed that acute inpatient corticosteroid use was associated with increased mortality (OR 2.22, 95% CI 1.26-3.90), however this result appeared to have been biased by confounding via indication. One subgroup analysis indicated an association between immunosuppressant use and susceptibility to COVID-19 among case control and cross-sectional studies (OR 1.29, 95% CI 1.19-1.40) but this was not found with cohort studies (OR 1.11, 95% CI 0.86-1.43). Studies which adjusted for multiple confounders showed that people taking angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) required a lower level of care (OR 0.85, 95% CI 0.74-0.98). Furthermore, studies which combined these two drug groups in their analysis demonstrated an association with a lower mortality (OR 0.68, 95% CI 0.55-0.85).

Conclusions

We found minimal high quality or consistent evidence that any drug groups increase susceptibility, severity or mortality in COVID-19. Converse to initial hypotheses, we found some evidence that regular use of ACEIs and ARBs prior to infection may be effective in reducing the level of care required, such as requiring intensive care, in patients with COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2021.09.17.21262724: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power AnalysisConsidering the implications of random-effects models on statistical power (36), outcomes were deemed eligible for meta-analysis if more than four studies were identified that investigated the same drug group.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    This study consisted of a three-stage search strategy involving literature from four databases using the PECOS format (Population, Exposure, Comparison, Outcome, Study design): Embase, Medline, World Health Organization (WHO) COVID-19 Database (27) and National Institutes for Health (NIH) iSearch COVID-19 Portfolio (28).
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    Medline
    suggested: (MEDLINE, RRID:SCR_002185)
    We first searched the Medline and Embase databases simultaneously through Ovid, using a combination of Medical Subject Headings (MESH) and keywords, to capture papers related to the drugs already identified as potentially harmful in exploratory searches, as well as a string to identify new drugs. (Appendix 1: search terms).
    MESH
    suggested: (MeSH, RRID:SCR_004750)
    The third and final search was, therefore, undertaken for preprints on the NIH iSearch COVID-19 Portfolio database, which included Research Square, medRxiv, chemRxiv, arXiv, bioRxiv and Social Science Research Network.
    arXiv
    suggested: (arXiv, RRID:SCR_006500)
    bioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)

    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:
    Strengths and limitations: This rapid systematic review and meta-analysis has synthesised the best available evidence from the first few months of the pandemic for each of these drugs when taken by those with or at risk of COVID-19. This study has, within the limitations imposed by time and the unparalleled research publication rate, aimed to compile a comprehensive list of drugs that were hypothesized to be deleterious in peer-reviewed papers at the time of the searches. This review however has several limitations. The rapidity with which research is being produced and published affected our study in a number of ways. Firstly, we acknowledge that while a rapid review is justifiable on the grounds of swifter completion, it is less robust than a systematic review. Secondly, the studies included in this review were also completed within a short space of time in order to attempt to learn from clinical practice as quickly as possible. As a result of this, many papers that would be relevant to this review, including papers with stronger evidence and more robust methodology than some of those included may now be available. Finally, the research landscape is changing so quickly that the studies included in this review were all published prior to conducting the last search. This will bias our results towards the studies that were produced more quickly and in countries that experienced larger COVID-19 case numbers earlier on in this outbreak. These countries may have large differences...

    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.

    Results from scite Reference Check: We found no unreliable references.

    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 10.1101/2021.09.17.21262724v1 on medRxiv