Systematic benefit-risk assessment for the use of chloroquine or hydroxychloroquine as a treatment for COVID-19: Establishing a dynamic framework for rapid decision-making

  1. Vicki Osborne
  2. Miranda Davies
  3. Sandeep Dhanda
  4. Debabrata Roy
  5. Samantha Lane
  6. Alison Evans
  7. Saad Shakir

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Abstract

Objectives

Given the current pandemic, there is an urgent need to identify effective, safe treatments for COVID-19 (coronavirus disease). A systematic benefit-risk assessment was designed and conducted to strengthen the ongoing monitoring of the benefit-risk balance for chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-19 treatment.

Methods

The overall benefit-risk of the use of chloroquine or hydroxychloroquine as a treatment for COVID-19 compared to standard of care, placebo or other treatments was assessed using the Benefit-Risk Action Team (BRAT) framework. We searched PubMed and Google Scholar to identify literature reporting clinical outcomes in patients taking chloroquine or hydroxychloroquine for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance.

Results

Several potential key benefits and risks were identified for use of hydroxychloroquine or chloroquine in COVID-19 treatment. Currently available results did not show an improvement in mortality risk; Cox proportional hazard ratio (HR) for death between patients who received HCQ alone vs. neither hydroxychloroquine or azithromycin was 1.08 (95% CI 0.63-1.85). A further study compared the incidence of intubation or death (composite outcome) in a time to event analysis between patients who received HCQ vs. those patients who did not (adjusted Cox proportional HR 1.00 (95% CI 0.76-1.32)). Risk of cardiac arrest, abnormal electrocardiogram (ECG) and QT prolongation was greater among patients taking HCQ (with or without azithromycin) compared to standard of care in the same study.

Conclusions

Overall, based on the available data there does not appear to be a favourable benefit-risk profile for chloroquine or hydroxychloroquine compared to standard of care in treatment of severe COVID-19. As further data from clinical trials and real world use on these benefits and risks becomes available, this can be incorporated into the framework for an ongoing benefit-risk assessment.

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  1. Version published to 10.1101/2020.05.07.20093989v2 on medRxiv
  2. ScreenIT

    SciScore for 10.1101/2020.05.07.20093989: (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
    BRAT uses a six step iterative process to support the decision and communication of a Benefit-Risk Assessment: define decision context, identify outcomes, identify data sources, customise framework, assess outcome importance, and display and interpret key Benefit-Risk metrics [15,16].
    BRAT
    suggested: (BRAT, RRID:SCR_013159)

    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:
    5.1 Strengths and Limitations: Sample sizes for each outcome were limited to those available in the original studies and may not have adequate power to detect differences in risk between groups, especially where the outcomes examined were not the primary outcome of interest. The benefit-risk assessment is limited by the availability of data in the published literature. However, this assessment can be subsequently updated once further data from clinical trials are available. In addition, given the public health urgency of the COVID-19 pandemic, it is important to provide a systematic assessment of the benefits and risks of hydroxychloroquine and chloroquine treatments with evidence available to date and create a framework which can be used to rapidly update the assessment when further data are available. Data quality is not reflected in this benefit-risk assessment, though all data included were extracted from peer-reviewed manuscripts. Of note, a statement was issued by the International Society of Antimicrobial Chemotherapy [38] regarding the Gautret et al paper published in the international journal of antimicrobial agents [22]. The paper was not considered to meet the society’s expected standards and though it was peer-reviewed, the editor-in-chief was not involved in this process [38]. The paper by Rosenberg et al acknowledged that adverse events may have occurred at any time during hospitalisation regardless of when hydroxychloroquine was initiated, though hydroxychloroq...

    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.

  3. Version published to 10.1101/2020.05.07.20093989v1 on medRxiv