• Korbinian J Brand, Alexander Hapfelmeier, and Bernhard Haller.
• Institute of Medical Informatics, Statistics and Epidemiology, School of Medicine, Technical University of Munich, Munich, Germany.
• Clin Trials. 2021 Jun 1; 18 (3): 351-360.

BackgroundSubgroup analyses are frequently used to assess heterogeneity of treatment effects in randomised clinical trials. Inconsistent, improper and incomplete implementation, reporting and interpretation have been identified as ongoing challenges. Further, subgroup analyses were frequently criticised because of unreliable or potentially misleading results. More recently, recommendations and guidelines have been provided to improve the reporting of data in this regard.MethodsThis systematic review was based on a literature search within the digital archives of three selected medical journals, The New England Journal of Medicine, The Lancet and Circulation. We reviewed articles of randomised clinical trials in the domain of cardiovascular disease which were published in 2015 and 2016. We screened and evaluated the selected articles for the mode of implementation and reporting of subgroup analyses.ResultsWe were able to identify a total of 130 eligible publications of randomised clinical trials. In 89/130 (68%) articles, results of at least one subgroup analysis were presented. This was dependent on the considered journal (p < 0.001), the number of included patients (p < 0.001) and the lack of statistical significance of a trial's primary analysis (p < 0.001). The number of reported subgroup analyses ranged from 1 to 101 (median = 13). We were able to comprehend the specification time of reported subgroup analyses for 71/89 (80%) articles, with 55/89 (62%) articles presenting exclusively pre-specified analyses. This information was not always traceable on the basis of provided trial protocols and often did not include the pre-definition of cut-off values for the categorization of subgroups. The use of interaction tests was reported in 84/89 (94%) articles, with 36/89 (40%) articles reporting heterogeneity of the treatment effect for at least one primary or secondary trial outcome. Subgroup analyses were reported more frequently for larger randomised clinical trials, and if primary analyses did not reach statistical significance. Information about the implementation of subgroup analyses was reported most consistently for articles from The New England Journal of Medicine, since it was also traceable on the basis of provided trial protocols. We were able to comprehend whether subgroup analyses were pre-specified in a majority of the reviewed publications. Even though results of multiple subgroup analyses were reported for most published trials, a corresponding adjustment for multiple testing was rarely considered.ConclusionCompared to previous reviews in this context, we observed improvements in the reporting of subgroup analyses of cardiovascular randomised clinical trials. Nonetheless, critical shortcomings, such as inconsistent reporting of the implementation and insufficient pre-specification, persist.

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