Subgroup analyses of randomized clinical trials in heart failure: facts and numbers

Vidic, Andrija; Chibnall, John T.; Goparaju, Niharika; Hauptman, Paul J.

doi:10.1002/ehf2.12093

Cited by 10 publications

(10 citation statements)

References 16 publications

(28 reference statements)

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“…Two recent reviews investigated subgroup analysis quality in low back pain management trials 29,30 and reported the failure to specify the subgroup hypotheses a prior as a common problem in trials, which is also consistent with our findings. Vidic et al 10 reviewed phase III cardiovascular RCTs with subgroup analysis, concluding that subgroup analysis was reported with several shortcomings, including lack of prespecification and testing of a large number of subgroups without the use of the statistically appropriate test for interaction. All these studies reported the failure to specify the subgroup hypotheses, the many subgroup analyses conducted and underuse of interaction tests as common problems in trials, which is consistent with our findings.…”

Section: Discussionmentioning

confidence: 99%

“…Subgroup analysis has the potential to generate hypotheses for further prospective investigation 10 and its exploratory nature requires results to be confirmed in a new study to ensure the findings have statistical reliability. However, confirmatory studies are generally never carried out and decisions in clinical practice are made despite this lack of information.…”

Section: Introductionmentioning

confidence: 99%

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Subgroup analysis in haematologic malignancies phase III clinical trials: A systematic review

Gutiérrez

Ramallo

Flores-Moreno

et al. 2020

Brit J Clinical Pharma

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Aims To assess the appropriateness of the use and interpretation of subgroup analysis in haematology randomized clinical trials (RCTs). Method A systematic review of Medline, including haematology phase III RCTs published between January 2013 and October 2019, was carried out to identify reported subgroup analysis. Information related to trial characteristics, subgroup analysis and claims of subgroup difference were collected. Results The initial search identified 1622 studies. A total of 98 studies reporting subgroup analyses were identified. Of those, 24 RCT reported 46 claims of subgroup difference. Among them, 44 were claims for the primary outcome, of which 25 were considered strong claims and 17 were considered suggestions of a possible effect. Authors included subgroup variables for the primary outcome measured at baseline for 38 claims (n = 86.36%), used a subgroup variable as a stratification factor at randomization for 15 (34.09%), clearly prespecified their hypothesis for 11 (25%), the subgroup effect was one of a small number of hypothesised effects tested (≤ 5) for 17 (38.64%), carried out a test of interaction that provide statistically significant for 18 (40.91%), documented replication of a subgroup effect with previously related studies for 11 (25%), identified the consistency of a subgroup effect across related outcome for 10 (22.72%) and provided a biological rationale for the effect for 8 (18.18%). Of the 44 claims for the primary outcome, 34 (77.27%) met four or fewer of the 10 credibility criteria. Conclusion The subgroup claims reported in haematology RCTs lack credibility, even when the claims are strong. Information about subgroup difference should be interpreted cautiously.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Subgroup analysis in haematologic malignancies phase III clinical trials: A systematic review

Gutiérrez

Ramallo

Flores-Moreno

et al. 2020

Brit J Clinical Pharma

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“…Randomised clinical trials (RCTs) in cardiovascular disease often include subgroup analyses. 1 – 3 These are used to assess heterogeneity of treatment effects, concerning primary, secondary or adverse trial outcomes. 4 – 6 Corresponding investigations are generally based on the assumption that certain subgroups of patients may benefit more or less from a studied intervention.…”

Section: Introductionmentioning

confidence: 99%

A systematic review of subgroup analyses in randomised clinical trials in cardiovascular disease

2021

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Background: Subgroup 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. Methods: This 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. Results: We 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. Conclusion: Compared 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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“…This is not a call for additional subgroup analyses; they have limitations. 14 Rather, as in the case with ivabradine, we should try to deliver as much precision as we can to our list of indications (and contraindications), thereby maximizing benefit without exposing patients to undue costs and potential harm.…”

Section: Concluding Thoughtsmentioning

confidence: 99%

Variations on a Precision Medicine Theme

Hauptman

Gong

Vidic

2016

Circ: Heart Failure

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Subgroup analyses of randomized clinical trials in heart failure: facts and numbers

Cited by 10 publications

References 16 publications

Subgroup analysis in haematologic malignancies phase III clinical trials: A systematic review

Subgroup analysis in haematologic malignancies phase III clinical trials: A systematic review

A systematic review of subgroup analyses in randomised clinical trials in cardiovascular disease

Variations on a Precision Medicine Theme

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