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. 2025 Jun 27:28:e250035.
doi: 10.1590/1980-549720250035. eCollection 2025.

Prevalence of bias attributable to composite outcome in clinical trials published in 2019-2020: a systematic review

José Mário Nunes da Silva  1 , Juliana Ferreira Souza Conceição  2 , Paula Camila Ramírez  3 , Christian Leonardo Diaz-León  4 , Fredi Alexander Diaz-Quijano  5
Affiliations

Prevalence of bias attributable to composite outcome in clinical trials published in 2019-2020: a systematic review

José Mário Nunes da Silva et al. Rev Bras Epidemiol. .

Abstract
in English, Portuguese

Objective: The aim of this study was to investigate the prevalence of bias attributable to composite outcome (BACO) in clinical trials.

Methods: We searched PubMed for randomized clinical trials where the primary outcome was a binary composite that included all-cause mortality among its components from January 1, 2019, to December 31, 2020. For each trial, the BACO index was calculated to assess the correspondence between effects on the composite outcome and mortality. This systematic review was registered in PROSPERO (CRD42021229554).

Results: After screening 1,076 citations and 171 full-text articles, 91 studies were included from 13 different medical areas. The prevalence of significant or suggestive BACO among the 91 included articles was 25.2% (n=23), including 12 with p<0.005 and 11 with p between 0.005 and <0.05. We observed that in 17 (73.9%) of these 23 studies, the BACO index value was between 0 and <1, indicating an underestimation of the effect. The other six studies showed negative values (26.1%), indicating an inversion of the association with mortality. None of the studies showed significant overestimation of the association attributable to the composite outcome.

Conclusion: These findings highlight the need to predefine guidelines for interpreting effects on composite endpoints based on objective criteria such as the BACO index.

Objetivo:: Investigar a prevalência de viés atribuível ao desfecho composto (BACO) em ensaios clínicos.

Métodos:: Buscamos no PubMed ensaios clínicos randomizados em que o desfecho primário fosse um composto binário que incluísse mortalidade por todas as causas entre seus componentes, entre 1° de janeiro de 2019 e 31 de dezembro de 2020. Para cada ensaio, o índice BACO foi calculado para avaliar a correspondência entre os efeitos sobre o desfecho composto e aqueles sobre a mortalidade. Esta revisão sistemática foi registrada no PROSPERO (CRD42021229554).

Resultados:: Após triagem de 1.076 citações e 171 artigos completos, 91 estudos foram incluídos, abrangendo 13 áreas médicas diferentes. A prevalência de BACO significativo ou sugestivo entre os 91 artigos incluídos foi de 25,2% (n=23), incluindo 12 com p<0,005 e 11 com p entre 0,005 e <0,05. Observamos que em 17 (73,9%) desses 23 estudos, o valor do índice BACO estava entre zero e <1, indicando uma subestimação do efeito. Nos outros seis estudos, os valores foram negativos (26,1%), indicando uma inversão da associação com a mortalidade. Nenhum dos estudos apresentou superestimação significativa da associação atribuível ao desfecho composto.

Conclusão:: Esses achados ressaltam a necessidade de pré-definir diretrizes para interpretação dos efeitos em desfechos compostos com base em critérios objetivos, como o índice BACO.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTERESTS: nothing to declare

Figures

Figure 1
Figure 1. Flowchart of the study identification and selection.
See this image and copyright information in PMC

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