Advertisement

Heterogeneity in multicentre trial participating centers: lessons from the TOPCAT trial on interpreting trial data for clinical practice

  • Mathew Mercuri
    Correspondence
    Corresponding Author at: Division of Emergency Medicine, Department of Medicine, McMaster University, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2. Tel.: +1 905 521 2100.
    Affiliations
    Department of Medicine, Division of Emergency Medicine, McMaster University, Hamilton, Canada

    Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, and Victoria College, University of Toronto, Toronto, Canada

    Department of Philosophy, University of Johannesburg, Auckland Park, South Africa
    Search for articles by this author
  • Amiram Gafni
    Affiliations
    Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
    Search for articles by this author
Published:November 11, 2022DOI:https://doi.org/10.1016/j.jclinepi.2022.11.008

      Abstract

      Objectives

      Randomized controlled trials (RCTs) are considered a “gold standard” of evidence, provided they meet rigorous standards in design and execution. Recently, some investigators of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial advocate reanalysis of results, deviating from the statistical analysis plan. We briefly review the rationale by the TOPCAT investigators and implications for interpreting trial data.

      Study Design and Setting

      Critical examination of existing literature.

      Results

      The TOPCAT trial showed variation in patient characteristics and outcomes among different geographic regions. The investigators suggest that the observed variation indicated unreliable data, warranting deviation from protocol. That lead to claims of therapeutic effectiveness for populations in select regions. We suggest that some variation is expected in multicentre RCTs and argue that discriminating between natural variation and unreliable data can be challenging. Thus, the warrant for deviation from protocol is not clear.

      Conclusion

      The TOPCAT investigators highlight important concerns about heterogeneity in RCT samples and how that may impact our interpretation of the results. If we are to maintain rigor in the RCT methodology and preserve its status as a reliable form of evidence for clinical practice, we must carefully consider when it is appropriate to deviate from a protocol when analyzing and interpreting trial data.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Clinical Epidemiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Pfeffer M.A.
        • Clagget B.
        Behind the scenes of TOPCAT – Bending to inform.
        NEJM Evid. 2022; 1: 1-7
        • Pitt B.
        • Pfeffer M.A.
        • Assmann S.F.
        • Boineau R.
        • Anand I.S.
        • Claggett B.
        • et al.
        Spironolactone for heart failure with preserved ejection fraction.
        N Engl J Med. 2014; 370: 1383-1392
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • Butler J.
        • Casey D.E.
        • Colvin M.M.
        • et al.
        2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines and the heart failure society of America.
        Circulation. 2017; 136: e137-e161
        • Wennberg J.E.
        Time to tackle unwarranted variations in practice.
        Br Med J. 2011; 342: 687-690
        • Mercuri M.
        • Gafni A.
        Medical practice variations: what the literature tells us (or does not) about what are warranted and unwarranted variations.
        J Eval Clin Pract. 2011; 17: 671-677
        • Mercuri M.
        • Gafni A.
        Reflecting on evidence based medicine, person centered medicine, and small area variations: how contemporary frameworks for medicine address (or not) the needs of the individual patient.
        Eur J Person Centered Healthc. 2018; 6: 454-461
        • Dagenais G.R.
        • Leong D.P.
        • Rangarajan S.
        • Lanas F.
        • Lopez-Jaramillo P.
        • Gupta R.
        • et al.
        Variations in diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): a prospective cohort study.
        Lancet. 2020; 395: 785-794
        • Wennberg J.E.
        Forty years of unwarranted variation – and still counting.
        Health Policy. 2014; 114: 1-2
        • Mercuri M.
        • Birch S.
        • Gafni A.
        Using small area variations to inform healthcare service planning: what do we “need” to know?.
        J Eval Clin Pract. 2013; 19: 1054-1059
        • Schulz K.F.
        • Altman D.G.
        • Moher D.
        CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials.
        BMJ. 2010; 340: c332