NSAID use and clinical outcomes in COVID-19 patients: a 38-center retrospective cohort study

  1. Justin T. Reese
  2. Ben Coleman
  3. Lauren Chan
  4. Hannah Blau
  5. Tiffany J. Callahan
  6. Luca Cappelletti
  7. Tommaso Fontana
  8. Katie R. Bradwell
  9. Nomi L. Harris
  10. Elena Casiraghi
  11. Giorgio Valentini
  12. Guy Karlebach
  13. Rachel Deer
  14. Julie A. McMurry
  15. Melissa A. Haendel
  16. Christopher G. Chute
  17. Emily Pfaff
  18. Richard Moffitt
  19. Heidi Spratt
  20. Jasvinder A. Singh
  21. Christopher J. Mungall
  22. Andrew E. Williams
  23. Peter N. Robinson

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Abstract

Background

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, fever, and inflammation but have been associated with complications in community-acquired pneumonia. Observations shortly after the start of the COVID-19 pandemic in 2020 suggested that ibuprofen was associated with an increased risk of adverse events in COVID-19 patients, but subsequent observational studies failed to demonstrate increased risk and in one case showed reduced risk associated with NSAID use.

Methods

A 38-center retrospective cohort study was performed that leveraged the harmonized, high-granularity electronic health record data of the National COVID Cohort Collaborative. A propensity-matched cohort of 19,746 COVID-19 inpatients was constructed by matching cases (treated with NSAIDs at the time of admission) and 19,746 controls (not treated) from 857,061 patients with COVID-19 available for analysis. The primary outcome of interest was COVID-19 severity in hospitalized patients, which was classified as: moderate, severe, or mortality/hospice. Secondary outcomes were acute kidney injury (AKI), extracorporeal membrane oxygenation (ECMO), invasive ventilation, and all-cause mortality at any time following COVID-19 diagnosis.

Results

Logistic regression showed that NSAID use was not associated with increased COVID-19 severity (OR: 0.57 95% CI: 0.53–0.61). Analysis of secondary outcomes using logistic regression showed that NSAID use was not associated with increased risk of all-cause mortality (OR 0.51 95% CI: 0.47–0.56), invasive ventilation (OR: 0.59 95% CI: 0.55–0.64), AKI (OR: 0.67 95% CI: 0.63–0.72), or ECMO (OR: 0.51 95% CI: 0.36–0.7). In contrast, the odds ratios indicate reduced risk of these outcomes, but our quantitative bias analysis showed E-values of between 1.9 and 3.3 for these associations, indicating that comparatively weak or moderate confounder associations could explain away the observed associations.

Conclusions

Study interpretation is limited by the observational design. Recording of NSAID use may have been incomplete. Our study demonstrates that NSAID use is not associated with increased COVID-19 severity, all-cause mortality, invasive ventilation, AKI, or ECMO in COVID-19 inpatients. A conservative interpretation in light of the quantitative bias analysis is that there is no evidence that NSAID use is associated with risk of increased severity or the other measured outcomes. Our results confirm and extend analogous findings in previous observational studies using a large cohort of patients drawn from 38 centers in a nationally representative multicenter database.

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  1. Version published to 10.1186/s12985-022-01813-2
  2. ScreenIT

    SciScore for 10.1101/2021.04.13.21255438: (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 Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Using the DrugCentral resource22, we developed the following list of representative indications: osteoarthritis, rheumatoid arthritis, angina pectoris, migraine, myocardial infarction, pain, headache, and fever (OMOP concept id codes in Supplemental Table S2).
    DrugCentral
    suggested: (DrugCentral, RRID:SCR_015663)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Strengths and limitations of this study: Observational studies such as retrospective EHR cohort analysis are subject to confounding. In the case of our study, the decision of whether to treat a patient with a COX inhibitor could in principle be correlated with the outcome of interest (COVID-19 severity). We applied two strategies to mitigate confounding: (i) analysis of subcohorts according to indication, and (ii) propensity matching. However, in observational studies a risk of residual confounding persists because the efficacy of propensity matching is limited to known and measured factors. Exposure to the drugs of interest, most of which are available without a prescription, was likely to be captured incompletely in the EHR data used in the analysis. Thus, it is possible that there was unrecorded use of COX inhibitors in the untreated group. Our study uses a five-level ordinal measure of COVID-19 outcome that may allow increased sensitivity compared with some previous efforts that use only COVID-19 mortality to measure outcome.

    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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  3. Version published to 10.1101/2021.04.13.21255438 on medRxiv