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
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References
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Article info
Publication history
Published online: November 11, 2022
Accepted:
November 8,
2022
Footnotes
Funding: None.
Declaration of interest: None.
Author contributions: Both authors contributed to the conception of the manuscript and analysis. MM drafted the article. Both authors revised it for critically important intellectual content and approved the final version to be submitted.
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
