Prevalence use of nonsteroidal anti-inflammatory drugs in the general population with COVID-19 and associated COVID-19 risk, hospitalization, severity, death, and safety outcomes: A systematic review and meta-analysis

  1. Huilei Zhao
  2. Shanshan Huang
  3. Kaibo Mei
  4. Wen Shao
  5. Jing Zhang
  6. Jianyong Ma
  7. Wengen Zhu
  8. Yuan Jiang
  9. Peng Yu
  10. Xiao Liu

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Abstract

Introduction

Recent reports of potential harmful effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with Corona Virus Disease 2019 (COVID-19) have provoked great concern. Therefore, the safety of NSAIDs is still questioned.

Methods

We searched the PubMed, EMBASE, Cochrane Library and Web of Science databases from December 2019 to January 2021 to examine use prevalence for NSAIDs in general, as well as associated COVID-19 risk and outcomes. This study has been registered with PROSPERO (CRD42019132063)

Results

We included 25 studies with a total of 101,215 COVID-19 patients. The use of NSAIDs in COVID-19 patients reached 19%. Exposure to NSAIDs was not associated with significantly increased risk of developing COVID-19 (odds ratio [OR]=0.98, 95% confidence interval [CI]: 0.78-1.24; I 2 =82%), hospitalization (OR=1.06, 95%CI: 0.76-1.48; I 2 =81%), mechanical ventilation (OR=0.71, 95%CI: 0.47-1.06; I 2 =38%), and length of hospital stay. Moreover, use of NSAIDs was significantly associated with better outcomes, including severity of COVID-19 (OR=0.79, 95%CI: 71-0.89; I 2 =0%) and death (OR=0.68, 95%CI: 0.52-0.89; I 2 =85%) in patients with COVID-19. Regarding safety outcomes, exposure to NSAIDs was associated with increased risk of stroke (OR=2.32, 95%CI: 1.04-5.2; I 2 =0%), but not with myocardial infraction (OR=1.49; p =0.66; I 2 =0%), overt thrombosis (OR=0.76, p=0 . 50 ; I 2 =28%) and major bleeding ( p =0.61).

Conclusion

Based on current evidence, exposure to NSAIDs is not linked to increased odds or exacerbation of COVID-19 in the general COVID-19 population. Furthermore, administration of NSAIDs might have better outcomes and survival benefits in the general COVID-19 population, although potentially increasing the risk of stroke. Use of NSAIDs might be safe and beneficial in COVID-19. Future observational and randomized control trials are needed for further confirmation.

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  1. ScreenIT

    SciScore for 10.1101/2021.05.01.21256428: (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
    Literature search: Two independent researchers (Liu Xiao and Shanshan Huang) searched the PubMed, Cochrane Library, Web of Science, EMBASE, and MedRxiv (https://www.medrxiv.org/) databases from December 2019 to January 2021 for relevant studies without any language restrictions.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Cochrane Library
    suggested: (Cochrane Library, RRID:SCR_013000)
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)
    Statistical analysis: Meta-analysis was performed using international STATA15.0 (StataCorp, College Station, Texas) and RevMan5.3 (Review Manager [RevMan], version5.3, Cochrane Collaboration) software.
    StataCorp
    suggested: (Stata, RRID:SCR_012763)
    Cochrane Collaboration
    suggested: None
    The calculation and aggregation of natural logarithm of the OR (log [OR]) and its standard error (SElog [OR]) were conducted by Revman 5.3.
    Revman
    suggested: (RevMan, RRID:SCR_003581)

    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:
    Study strengths and limitations: The greatest strength of this study was its large sample size, and all trials were general population-based. We examined the use rate of NSAIDs in COVID-19 cases and comprehensively assessed the related outcomes, including the risk of COVID-19, hospital admission, severity, mechanical ventilation and death, as well as safety outcomes. As readily available and inexpensive drugs, these results revealed benefits for the clinical use of NSAIDs during the COVID-19 pandemic. We recognize possible limitations as well. 1) There are intrinsic limitations associated with any observational study, which is unable to prove a causal relationship. 2) The included individuals were adult, and the effects of NSAIDs in young individuals and children should be further studied. 3) Measured and unmeasured factors, such as various underlying diseases, may have influenced the above results. For example, it is thought that there is a great gender difference in COVID-19. However, the limited data prevented sex-specific subgroup analysis. 4) Some data, including age and specific drug doses, were incomplete in most included studies and could not be further analyzed. However, Wong et al.[40] reported that high or low ibuprofen or naproxen is not linked to increased risk of COVID-19 death in the general population, which suggests NSAID use is safe at common clinical doses. 5) Significant heterogeneity was observed across the included studies, which might result from betwee...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT0432563339Trial number did not resolve on clinicaltrials.gov. Is the number correct?NA
    NCT0438276840Trial number did not resolve on clinicaltrials.gov. Is the number correct?NA
    NCT0433462941Trial number did not resolve on clinicaltrials.gov. Is the number correct?NA
    NCT04344457RecruitingEvaluate the Efficacy and Safety of Oral Hydroxychloroquine,…

    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 10.1101/2021.05.01.21256428 on medRxiv